High HDL levels, and particularly high HDL-to-total cholesterol ratios, in the general population, are associated with lower CV risk.
However, therapeutic interventions to raise HDL have had poor outcomes, and there's no evidence that unusual diets targeting this marker would fare better. Moreover, multiple Mendellian randomization studies demonstrate that a genetic propensity to higher HDL levels isn't protective, so belief that low HDL is in the causal chain for most CVD has taken a considerable blow.
Association is not causation. There may be other factors (exercise, obesity and factors hitherto unidentified) that effect both HDL and CVD outcomes, that are responsible for the epidemiological association. In the drawing below I speculated that they might be exercise and obesity, but it should just read 'other factors'. The absence of arrows between HDL, HDL targeted therapy, genetic propensity, and CVD outcomes is intentional.
Briel, M., Ferreira-Gonzalez, I., You, J. J., Karanicolas, P. J., Akl, E. A., Wu, P., ... & Guyatt, G. H. (2009). Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. Bmj, 338.
Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths.
Voight, B. F., Peloso, G. M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M. K., ... & Ingelsson, E. (2012). Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. The Lancet,380(9841), 572-580.
Genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
Holmes, M. V., Asselbergs, F. W., Palmer, T. M., Drenos, F., Lanktree, M. B., Nelson, C. P., ... & Gaunt, T. R. (2014). Mendelian randomization of blood lipids for coronary heart disease. European heart journal, eht571.
Neither the restricted allele score nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use showed a robust association... The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
The restricted HDL-C allele score did not show an association with CHD. The restricted HDL-C allele score was more selective for HDL-C (showing only a very weak association with triglycerides and no effect on LDL-C), but also explained less of the variance of the index trait, HDL-C (even when compared with other restricted scores), so it remains uncertain if this attenuation in the effect estimate implies that an intervention that solely modifies HDL-C would not reduce risk of CHD, or whether it is due to a reduction in statistical power. This former interpretation is in agreement with findings from our unrestricted allele score adjusted for triglycerides, and with a previous multiple SNPs Mendelian randomization analysis that, using different genetic instruments, also failed to identify a clear causal role of HDL-C in CHD.
As you might imagine, these results have caused some consternation within the cardiology community:
Ng, D. S., Wong, N. C., & Hegele, R. A. (2013). HDL—is it too big to fail?.Nature Reviews Endocrinology, 9(5), 308-312.
5 years ago, few could have envisioned recent developments swirling around HDL. Conceivably, given the past economic and intellectual investments into the HDL hypothesis, it can now only be repealed at a very high cost. Furthermore, although difficult to quantify, some important psychological factors may have been at play. These include confirmation bias, as evidenced by the tendency to seek out opinions and facts that support a priori beliefs about the HDL hypothesis; selective recall, as evidenced by the habit of sometimes remembering only facts and experiences that reinforce strongly-held assumptions about HDL; biased evaluation, as evidenced by quick acceptance of data that support the HDL hypothesis, but close scrutiny and more easy rejection of contradictory data; and, lastly, group thinking among key opinion leaders, as evidenced by the pressure to agree with others in publications, public conferences or team-based settings. All of these biases have worked in recent years towards reinforcing the belief that HDL and CVD are linked causally to each other, and may have contributed to the current situation in which HDL indeed seems too big to fail.
Perhaps someday we'll see a prospective trial of dietary interventions to raise HDL with hard outcome (CVD event) endpoints, and perhaps this will demonstrate dietary interventions succeed where therapeutic interventions failed. But I suspect HDL, like homocysteine and C-reactive protein, may be another case where people are treating the marker and not the disease.
On the other hand, many HDL increasing diets also reduce triglycerides, and the Mendelian randomization studies are strongly supporting a causal role for triglyceride levels in CVD, as well as for Lp(a), though with smaller effect sizes than that for LDL. Based on these most recent reports, it appears a diet with lowering LDL as its first priority while mindful of triglycerides and Lp(a) as secondary priorities may be the way forward.
As to my comment about nicotinic acid, it looks like all the benefits are below the horizontal line:
Edited by Darryl, 28 June 2014 - 04:21 AM.