Framingham: Low HDL, in Isolation, Not a CV Risk Predictor

Veronica Hackethal, MD

May 26, 2016

FRAMINGHAM, MA — Long-term findings from a famous cohort study challenge the idea that low HDL-cholesterol levels predict raised cardiovascular risk independently of other blood lipid markers and add to doubts about HDL-C per se as a target for therapy[1].

It suggests that the association between future CV risk and levels of HDL-C, as currently measured in practice, is modified by LDL cholesterol and triglycerides. The predictive power of HDL-C is diminished when measures of either or both of the other markers are high.

"We're not taking away the importance of HDL. We're just putting it into perspective. If you have low HDL but everything else is normal, your risk of CV disease is not elevated," according to lead author Dr Michael Miller (University of Maryland School of Medicine, Baltimore).

"If your patient has a high HDL, the risk of CV disease tends to remain low, compared with low HDL at similar levels of risk," Miller told heartwire from Medscape. "However, the high-HDL advantage is erased if LDL-C and triglyceride levels exceed 100 mg/dL. People with a high HDL should not be falsely reassured that their risk of heart disease is necessarily low."

Findings from the original Framingham cohort helped establish that HDL-C levels, by themselves, are inversely correlated with CV risk, but their triglycerides weren't consistently measured, according to the report. But triglycerides were followed in the subsequent cohort.

The new analysis, published May 12, 2016 in Circulation: Cardiovascular Quality and Outcomes, covers 3590 participants of the Framingham Heart Study Offspring Cohort, initially without known CV disease, followed from 1987 to 2011. Low levels of HDL-C (<50 mg/dL in women and <40 mg/dL in men) were defined as isolated if both triglycerides and LDL-C were optimal (<100 mg/dL). That was observed in 2.3% of the cohort.

CV risk was sharply elevated among participants with low HDL-C when levels of the other markers were not optimal, compared with those with isolated HDL-C, even after adjustment for age at initial lipid testing, sex, diabetes, hypertension, and smoking.

The odds ratio (OR) for CV disease at follow-up among those with low HDL-C was:

  • 1.3 (95% CI 1.0–1.6) with LDL-C ≥100 mg/dL and triglycerides <100 mg/dL.

  • 1.3 (95% CI 1.1–1.5) with LDL-C <100 mg/dL and triglycerides ≥100 mg/dL.

  • 1.6 (1.2–2.2) with triglycerides and LDL both ≥100 mg/dL.

The results were similar for "high" levels of triglycerides (≥150 mg/dL) and LDL-C (≥130 mg/dL).

Elevated HDL-C was associated with a 20% to 40% drop in CV risk compared with isolated low HDL-C. But there was no significant risk effect when both triglycerides and LDL were 100 mg/dL or higher.

Whether or not HDL-C is a good treatment target to pursue remains unclear, according to Miller. It's not uncommon to meet patients with isolated HDL-C, many of whom are young middle-aged men who are otherwise healthy and in good physical shape. Such patients, he said, would have been recommended aerobic exercise and/or niacin. However, results from the AIM-HIGH and HPS2-THRIVE trials suggested that increasing HDL with niacin does not have much of an effect on CV risk.

Also, he said, the ACCELERATE study, which looked at the cholesterol esterase transfer protein (CETP) inhibitor evacetrapib (Eli Lilly), suggested that raising HDL-C and improving cholesterol efflux (the first step in cholesterol transport) did not decrease CV risk. That study suggests that the correct assay to measure cholesterol function may not even be being used, according to Miller.

"While we still believe that HDL-C plays a pivotal role in reverse cholesterol transport, we have yet to prove that either raising HDL-C levels or improving its function reduces CVD risk," he said.

Role of HDL Subtypes

Since 2011, European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) lipid guidelines have recommended that HDL-C no longer be a target for lipid-lowering therapy, Dr Maciej Banach (Medical University of Lodz, Poland) told heartwire in an email.

One problem with some CETP-inhibitor trials is that they included patients at relatively high CV risk, so the results may not apply to a primary-care population, he said. "We might hypothesize that HDL might still be an important biomarker of CVD in the group of relatively healthy patents in primary prevention."

"Dysfunctional HDL might be an important risk factor of CV disease with proatherogenic properties," he explained. "This impaired HDL functionality might be observed in patients with CV risk factors like smoking, obesity, and/or diabetes mellitus and especially in patients with established CV disease and chronic kidney disease."

Moreover, he said, it's increasingly appreciated that HDL-C assays measure a range of HDL subtypes and that the "wrong" kind of HDL-C may be being measured. "It is still largely disputed which subtypes are most beneficial. Some of the subtypes are not associated with reduced CV risk. Some may even increase this risk and might be considered dysfunctional HDL," according to Banach. But the current study can't address that, because HDL-C was not broken down by subtypes.

Banach said his group is currently conducting the Investigating Dysfunctional HDL (DYS-HDL) study[2] in selected groups of patients at high risk of cardiovascular events. It's examining subtypes of HDL with impaired antiatherogenic function and their predictive role for clinical events in a group of patients with varying CV risk. He said results are expected in 2017.

The study was funded by the National Institutes of Health and a Veterans Affairs Merit Award. The authors and Banach report no relevant financial disclosures.

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