Defining the Cardiovascular Risk of Hypertriglyceridemia: Reviewing the Guidelines

Dr. Ballantyne: Now Mike Miller is next. Let's get Mike up here. It's really a great group here tonight because Ernie has been studying the effects of dietary and omega-3s for quite a number of years, and Mike's had an interest in triglycerides going back a long time here. Mike made some very interesting observations in redefining what was really a normal triglyceride level in terms of at least cardiovascular risk, and he's recently spent a lot of time and effort leading the AHA guideline paper on triglycerides, and he's going to review some of these data here. Mike is a Professor of Medicine, Epidemiology, and Preventive Medicine, and Director of the Center for Preventive Cardiology at the University of Maryland Medical Center.

Michael Miller, MD: Thank you very much, Christie. Great to be here. So I'll take up where Ernie left off -- he focused on omega-3s, and discussed the issues related to decreasing triglycerides, and I'm going to talk about the issue of triglycerides as it relates to heart disease risk. These are my disclosures.

I'm going to spend a few minutes actually 3.75 minutes for each of these 4 points, right?

Let's talk about the epidemiology of hypertriglyceridemia. I think this slide puts into perspective what we appreciate about the risk associated with elevated triglycerides. If you compare the upper tertile vs the lower tertile, using the logarithmic transformation, by and large, and controlling or stratifying in different groups, what you see is an elevated associated risk.

But more recently, when adjustments were made, some of that elevated risk was attenuated. If you adjust for age and sex, you still see that association, when you further adjust for non-lipid risk factors, the association does go down although it's still important. And then when you further adjust for other elements, including non-HDL, you essentially lose that association. Although I think many of us might argue that adjustment of non-HDL might be an overadjustment to the analysis.

Let's talk about what has transpired over the past 20 years based on the long-term observational NHANES database. What you see here basically is that triglyceride levels have either remained the same or have gone up in young individuals, so if you look at men and women under the age of 40 years, you tend to see an increase in the median triglyceride level nationally. When you go up to older aged groups here, you see that the levels in effect have either again stayed the same or have slightly gone down. Now the reasons for this are not clear. We've gone through this, Michael Waltz at the NHLBI, Neil Stone, and I have tried to get a better assessment but they didn't keep records because this is cross-sectional. Well, we think that the primary reason why the levels of triglycerides have gone down in older aged groups is because they are taking lipid-lowering medications, so that's a more likely contributor than in the younger aged groups.

ASR first question here. Which of the following groups has the highest prevalence of hypertriglyceridemia in the United States? Is it African Americans, European Americans, Mexican Americans, or Japanese Americans?

And 59% chose the right answer, Mexican Americans. Very good. In fact, let's review this.

This is again from the AHA statement that came out back in the spring. And here what we're comparing is basically prevalence levels of triglycerides at 100, 200, and then 500 mg/dL from 1988 to 1994 and then 1999 to 2008.You can see that the Mexican American group have the highest prevalence of hypertriglyceridemia in 1988-1994 and 1999-2008.

Now if we look at the prevalence of elevated triglycerides using the most recent analysis, what you find is that having a triglyceride of at least 150 mg/dL is fairly common. Nearly 1 in 3 adult men and women have it, and it's highest again among Hispanics/Latinos. Roughly 1 in 6 people in the United States have levels of at least 200 mg/dL, with approximately 1 in 5 men having a triglyceride level of at least 200 mg/dL. Then as you go to the higher levels -- exceeding 500 mg/dL -- only 1% are affected, although men have a higher prevalence than women. Almost 2% of those with these high levels are Hispanics/Latinos.

What I want you to see here is what actually surprised Neil Stone and me quite a bit. If you look down at men, and look down at the prevalence of triglycerides of at least 500 mg/dL, you see that really skewed group of Hispanics/Latinos. Middle-aged Hispanics/Latinos in the NHANES cohort had an approximate 9% prevalence rate of very high triglycerides of at least 500 mg/dL. We again asked Michael to check that several different ways and he did, and it came out that Hispanics/Latinos have a particular problem in the United States regarding hypertriglyceridemia.

Now, elevated triglyceride levels do increase the risk for coronary disease at all levels of LDL-C and this is from Gert Osman's group, the PROCAM study. Looking at all the regions of baseline LDL, those that had the highest levels of baseline triglycerides of at least 200 mg/dL compared with LDL-C levels, there the rates were always higher. At any level of LDL-C, having a high triglyceride level conferred elevated risk, which gets back to what Ernie was discussing -- that the association of mixed hyperlipidemia markedly raises the risk for coronary disease.

And then, of course, there's residual cardiovascular disease risk in a number of trials. You've probably seen this slide one way or another over the past number of years, but by and large, in all these statin-based trials, even with significant relative risk reduction of 20%-30% there's still a considerable risk associated with patients on statins.

This is from the PROVE-IT TIMI analysis showing that again, residual risk is associated with on-treatment triglyceride levels that were at least 200 mg/dL. I think it's very reasonable to consider that I haveto drive our patients' LDL-C levels down, but there is a still this associated risk with high triglyceride levels.

I'm not going to go through this in great detail since Ernie took you through it, but I again just want to point out that after eating a high fat meal, those chylomicrons are avidly broken down into those CMR chylomicrons remnants that can be taken up by vascular lung macrophages, and can contribute to the cholesterol burden in vascular lung macrophages as does LDL when it's modified. So remnant particles, whether they're chylomicrons derived from fat, from exogenous forms or VLDL remnants, can contribute to plague.

This just shows lipid accumulation in macrophages after incubation with chylomicron remnant-like proteins (CRLPs) that are labeled here. You can see the associated uptake in these particles.

Now that patient with insulin resistance I borrow from Ernie, the consequence of insulin resistance -- enhanced free fatty acid flux driving hepatic VLDL production, which in turn stimulates or upregulates a CTP -- so there is greater transfer of lipid, triglyceride, and cholesteryl ester, leading to the triglyceride-enriched HDL, which is believed to be less efficient in cholesterol efflux, as well as triglyceride-enriched LDL which is then avidly hydrolyzed by lipases to small dents and potentially more oxidizable particles. So in addition to the high triglyceride level serving as a marker for downstream production of CRLPs, there is also that association with hypertriglyceridemia with triglyceride-enriched HDL and small dense LDL.

This is from Melissa Austin's paper a number of years ago, showing the breakdown of the small dense LDL, in yellow, and the more buoyant LDL particles in orange. You can see that the breakpoint in terms of the relative percentages in the circulation of the LDL phenotype A or B is actually not particularly high. It's a triglyceride level somewhere around 100 mg/dL, give or take. So, if you have a patient that has a triglyceride of 200 mg/dL, the poor man's method would tell you that the majority of those individuals' LDL particles are going to be smaller and dense.

The algorithm from the statement is that we recommend screening with a non-fasting triglyceride level and a nonfasting triglyceride level. It's eating a relatively small amount of fat, which is up to about 15 g of fat. There is a relationship between the amount of fat intake and the likelihood of the postprandial triglyceride level, triglyceride-rich lipoprotein triglyceride with a hypoprotein response. So you have a patient who comes in, eats a small, relatively modest fatty meal, and then has a TG less than 100 mg/dL. The follow-up is recorded; they have TGs of at least 200 mg/dL, so we recommend a fasting panel, and then we have the different ranges here. What was added to this statement was an optimal level of less than 100 mg/dL, and that's really to represent a metabolic barometer of the ability to clear fat pretty well. So people that live with low triglyceride levels are probably those who are exercising and just have the ability to catabolize fat.

Let's take our ARS and ask the next question. Which of the following nutrition practices has the biggest triglyceride-lowering effect? Is it (1) 1% energy replacement with monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA) for carbs; (2) 1% energy replacement with MUFA, PUFA for trans fatty acid; (3) the addition of marine-derived omega-3 PUFA; (4) weight loss; or (5) implementing a Mediterranean-style diet vs a low-fat diet. Go right ahead.

So you've listened to Ernie, that was quite good, you paid attention. However, that's not the right answer, sorry. Actually, the right answer is number 4, weight loss.

This again is from the AHA statement, an approximate 5%-10% reduction of body weight lowers triglyceride level upward of about 20%; implementing a Mediterranean-style diet v low fat is about 10%-15% reduction; and a marine-derived PUFA, now the trick here is per gram, is 5%-10%. If I had said 4 g, then we would have been up there for sure, but it's per gram. A decrease in carbs 1% replacement is 1%-2% TG lowering, and then eliminating trans fatty acids, so you take them all in total and you can get a really nice reduction in TG, just by using these measures.

Obviously, medications listed here are also have a pretty good effect, anywhere from as low as 5%-10% up to 50%.

Now, a number of studies have earned this, although there has not to date been a specifically designated trial just taking hypertriglyceridemic individuals, and especially those with cardiovascular disease and then randomizing them to standard of care, plus or minus omega-3 for example, vs just the standard of care alone on event rates or for that matter any triglyceride-lowering therapy. There are fibrates, so you do have fibrate-based studies but the patients were not all hypertriglyceridemic to begin with. You had to extrapolate whether you're looking at some prespecified endpoints as in ACCORD or if you've taken some post hoc analyses. The bottom line is that patients who have elevated triglyceride levels and low HDL-C do tend to benefit from use of these therapies, and JELIS indicated a really nice effect in the primary endpoint and the lipid subgroup also had a 50% reduction in TG.

In summary, epidemiologic studies support high triglyceride levels as an important biomarker of cardiovascular risk; high triglyceride levels are quite prevalent in the United States, whether you use the cutoff point of 150 or 200 mg/dL residual; cardiovascular risk is high despite certain therapy. We have intensive lifestyle therapy, it can significantly rescue TG levels, and we still need that missing link to achieve TG lowering in hypertriglyceridemic patients who remain at risk. Will you benefit clinically? Thank you very much.