*Geek Box: Esters & Carboxylic Acids
In order to understand the differences in the type of omega-3 fatty acids used in these studies, it is important to a have a very brief chemistry rundown.
For example, the REDUCE-IT trial used an EPA ethyl ester. Most fats that we consumed through the diet, or even within supplements, are in the form of triglycerides, i.e., three fatty acids bound to a glycerol (which is a sugar alcohol) backbone, which may also be known as ‘esters’, as the reaction that condenses the fatty acids and glycerol together is known as ‘esterification’. For example, you may often see the term ‘free fatty acids’ [FFA] referred to as ‘NEFA’, i.e., ‘non-esterified fatty acids’.
All fats and oils are therefore esters of fatty acids and glycerol. An ethyl is a chemical group derived from ethanol, an alcohol. Therefore, an ‘ethyl ester’ form of omega-3 fish oils is formed when the long-chain fatty acids EPA and DHA are bound (esterified) to ethanol (rather than glycerol, which would form a triglyceride instead). An ethyl ester form of omega-3 supplement results in a more concentrated level of EPA and DHA than a triglyceride form supplement, which most commercially available fish oils are. The absorption of ethyl esters is similar to long-chain fatty acids, i.e., intestinal absorption and subsequent breakdown into free fatty acids. Consequently, their absorption is influenced by dietary fat content, and is lower on an empty stomach or with very low-fat meals.
As a result of the additional processing required, ethyl ester EPA and/or DHA is more expensive, and pharmaceutical-grade products agents that are not generally available. Carboxylic acids are something you’re likely familiar with – the acid in vinegar or vitamin C in oranges are carboxylic acids. Any fatty acid structure ends with a carboxyl group – carboxylic acid formulations of omega-3 are free fatty acid forms of EPA and DHA, i.e., they are not bound to either glycerol (triglycerides) or ethanol (ethyl esters). This means they are absorbed with greater efficiency, and have significantly higher bioavailability than ethyl ester forms of omega-3. This higher bioavailability has been assumed to mean that carboxylic acid forms of omega-3’s are “better”, but this may not necessarily be the case. As things stand, if we’re talking about the results from interventions, the evidence would favour ethyl ester forms of EPA.