Food Labeling: Health Claims and Label Statements: Omega-3 Fatty Acids and Coronary Heart Disease

ed by LSRO do not accurately represent the totality of publicly available scientific evidence. For example, in its proposal, FDA included five studies among normal subjects (Refs. 2, 6, 24, 73, and 143) and three studies among subjects with preexisting lipid or lipoprotein abnormalities (Refs. 18, 73, and 93) not included in the LSRO report that had data for effects of omega-3 fatty acids on plasma lipids or lipoproteins. FDA determined that seven studies that reported changes in total cholesterol had the most rigorous designs and the largest numbers of normal subjects. None of these seven studies (Refs. 6, 9, 14, 49, 54, 73, and 166) in normal subjects found a significant change in total cholesterol after fish oil supplementation. FDA found similar results with regard to hyperlipidemic subjects. Only two of these seven strongest studies in normal subjects were abstracted in the LSRO text, and two others were not cited at all by this report. LSRO did not distinguish between normal and hyperlipidemic subjects in its summary or conclusions. LSRO summarized the evidence on total cholesterol by stating, “Decreases in total cholesterol * * * have also been reported,” (emphasis added), without mentioning that the predominant finding is that there is no effect on total cholesterol. Similarly, FDA stated that the strongest studies among normal subjects (Refs. 6, 9, 14, 49, 54, 73, and 166) found no change in LDL cholesterol, and one reported an increase in LDL cholesterol (Ref. 54). Indeed, most studies on hypertriglyceridemic or hypercholesterolemic subjects reported an increase in LDL cholesterol, following fish oil supplementation (56 FR 60663 et. 60669). Consequently, FDA disagrees strongly with the summary statements in the LSRO report: Effects of fish oil upon LDL have been variable, in part because of different doses. In normolipidemic individuals, LDL has generally declined significantly. In some patients with primary hypercholesterolemia, consumption of fish (sic) has not resulted in altered plasma cholesterol levels; other studies have shown decreased cholesterol and LDL levels. (Emphasis added.) 32. Two comments stated that FDA had not considered all relevant data on HDL2 cholesterol, and cited additional Federal Register / Vol. 58, No. 3 / Wednesday, January 6, 1993 / Rules and Regulations 2691 studies that reported increased HDL2 cholesterol after fish oil supplementation. One comment stated that overall HDL cholesterol tends to rise, and cited a review paper by Harm (Ref 62). The LSRO report also concluded that HDL was increased by fish oil supplementation. FDA disagrees with the comment regarding the overall HDL cholesterol change after fish oil supplementation. The agency considered HDL changes separately for normal, healthy subjects and for hyperlipidemic subjects (56 FR 60663 at 60669). Nearly all studies on normal subjects found no significant change in HDL cholesterol level. Some investigators reported increased HDL2, but the data on HDL2 were equivocal. FDA also disagrees with the conclusions of the LSRO report regarding HDL cholesterol, because it does not represent the totality of publicly available scientific evidence. The LSRO summary states, “In some studios HDL concentrations have actually increased with consumption of fish oil” (emphasis added), not acknowledging that the balance of available scientific evidence on HDL indicates no change. In the review by Harris cited in the comment, the changes in HDL cholesterol in each study were weighted according to the number of subjects in the study, giving a per-subject change. This method of pooling data from different studies does not account for the variation of the response of subjects in each study, the amount of omega-3 fatty acids fed, the duration of feeding, or the source of the omega-3 fatty acids. Therefore, it must be considered only an estimate of the effects of omega-3 fatty acids on HDL cholesterol. Harris calculated the average HDL cholesterol change for normal subjects to be an increase of approximately 3 percent, a net change smaller than the usual variability in the test used to measure HDL. The agency agrees with the comment that not all HDLs data were considered in the proposed rule, although FDA noted (56 FR 60663 at 60669) that some studies among normal subjects found increases in the HDLs fraction of HDL cholesterol, and that these reports were the most promising changes in blood lipids. Of the six references cited by the comments as not Included among studies showing increased HDL cholesterol after onwge-3 fatty acids, two were published after the time period covered in the proposed rule (Refs. 235 and 252). One other paper not cited by FDA in its proposal, although it was published during 1988 (Ref. 291), dealt with insulin-dependent diabetics. The other three papers were cited by FDA in other contexts, but data from these papers regarding HDL2 cholesterol levels were not discussed (Refs. 1, 32, and 148). FDA reexamined those papers that it cited but from which it did not present data regarding HDL2, together with the newer papers. When fractions of HDL cholesterol have been reported, an increase has generally been found in the HDL2 fraction (Refs. 1, 32, 148, 235, 251, and 291), with a comparable decrease in the HDL3 fraction (Refs. 1, 235, and 251). This represents a shift within the HDL fractions toward a lipid-rich lipoprotein, and away from a proteinrich lipoprotein, similar to that reported for LDL, below. This shift has been reported when there is (Refs. 32, 148, 235, and 291) or is not (Refs. 1 and 251) a change in total HDL cholesterol. This raises the possibility that a shift occurred in other studies where total HDL was reported as not changed. However, the importance of the shift in subfractions of HDL is not clear. FDA noted in its proposal (56 FR 60663 at 60869) that there is evidence that the HDLs fraction is the one most closely linked to risk of CHD. However, the agency was unable to find evidence that there was significant scientific agreement that HDL2 was the fraction of HDL most closely associated with CHD. The National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLB1) consensus development conference on Triglyceride, High Density Lipoprotein and Coronary Heart Disease (Ref. 255), anticipated in the proposal (56 FR 60663 at 60664), concluded that, “It is not known to what extent these alterations of HDL contribute to atherogenesis,” Therefore, data on changes in HDL subtractions after increased consumption of omega-3 fatty acids do not provide a sufficient basis for a health claim, because there is not significant scientific agreement that HDL2 is directly related to risk of CHD. If the risk of CHD becomes linked with HDL2, these findings in normal subjects may be of great importance. 33. Many comments indicated that high triglycerides are causally related to decreased HDL, that triglycerides are an independent risk factor for CHD, or that statistical manipulations of data and imprecise measurements of triglycerides obscure the importance of triglycerides as a risk factor for CHD. One comment provided additional citations regarding the relationship between triglycerides and HDL, but these did not bear on risk of CHD. One comment stated that it was generally agreed that triglycerides were not independently associated with CHD. FDA disagrees with all but the last comment. FDA is aware that there has been, and still is, substantial interest in the potential role of triglycerides in the etiology of CHD (e.g., Ref. 208). Because of the continued interest, the relationship between triglycerides and CHD was the topic of a consensus development conference sponsored by NHLBI on February 26 through 28, 1992. NHLBI had previously addressed this topic in 1983 and concluded at that time that the relationship was controversial. The recent conference (Ref. 255) concluded, “For triglyceride, the data are mixed; although strong associations are found in some studies, the evidence on a causal relation is still incomplete. ” FDA agrees that the statistical methods previously used to study the relationship between triglycerides and CHD have lessened the likelihood that triglycerides would be found to be a significant, independent predictor of CHD. Furthermore, the agency believes that study design and analytic measurement methods have contributed to variation in triglycerides that may have resulted in reducing the statistical association between triglycerides and CHD. FDA believes that these sources of variation in triglycerides can be reduced by careful study design and standardized analytical measurement techniques, and also that clinical studies designed to lower triglycerides could provide a basis upon which to reconsider the importance of triglycerides in CHD. 34. Some comments stated that some very recent evidence from the Helsinki Heart Study supports a protective effect of lowering triglycerides, at least for a selected subpopulation of people with a high ratio of LDL cholesterol/HDL cholesterol and very high triglycerides. FDA agrees that fish oils reduce plasma triglycerides. In its proposal FDA wrote, “The predominant blood lipid effects offish oils * * * are decreased plasma triglycerides and VLDL. ” (56 FR 60663 at 60669.) In this regard FDA and LSRO were in agreement. The LSRO summary states, “The most striking effect is lowering of plasma triglyceride and VLDL