Could High HDL Cholesterol Increase the Risk of Death?

Maintaining an intermediate level of high-density lipoprotein cholesterol (HDL-C) is associated with lower mortality rates, according to a new study.

“The finding that high HDL-C is associated with increased risk of death was surprising,” said study author Ziyad Al-Aly, MD, FASN, of the Department of Internal Medicine, Division of Nephrology, VA St Louis Health Care System. “HDL-C was thought of as the good cholesterol, where more—or higher levels—would have a salutary effect.”
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Using a “big data approach,” the researchers built a cohort of 1,764,986 US male veterans with at least 1 estimated glomerular filtration rate (eGFR) from October 2003 to September 2004 and followed their cases until September 2013 or death.

They found patients with low HDL-C and a low eGFR had a higher burden of comorbid illnesses. Over a median of 9.14 years, 26,247 (40.11%), 109,222 (32.28%), 152,625 (29.22%), 113,785 (28.5%), and 139,803 (31.81%) participants with respective HDL-C levels of ≤25, >25 to <34, ≥34 to ≤42, >42 to <50, and ≥ 50 mg/dL died. In adjusted survival models, compared with the referent group of patients with low HDL-C (≤25 mg/dL), intermediate HDL-C levels (>25 to <34, ≥34 to ≤42, and >42 to <50 mg/dL) were associated with lower risk of death across all levels of eGFR. The lower risk was diluted in those with high HDL-C (≥50 mg/dL), and they saw risk of death similar to the referent category among those with an eGFR <30 and ≥90 mL/min/1.73 m². Analysis by HDL-C deciles and spline analyses suggested that relationship between HDL-C and death followed a U-shaped curve.

The investigators found a significant interaction between eGFR and HDL-C in that a lower eGFR attenuated the salutary association of HDL-C and risk of death. The presence of coronary artery disease attenuated the lower risk of high HDL-C and all-cause mortality in those with an eGFR of 60 mL/min/1.73 m² or greater.

“The findings may explain why clinical trials aimed at increasing HDL-C levels failed to show improvement in outcomes,” Dr Al-Aly said.

Future research will look to better understand why high HDL-C is associated with increased risk of death, he said. The researchers also would like to better characterize the cause of death in patients with high HDL-C.

—Mike Bederka

Reference:

Bowe B, Xie Y, Xian H, Balasubramanian S, Zayed MA, Al-Aly Z. High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. veterans [published online August 11, 2016]. Clin J Am Soc Nephrol. doi:10.2215/CJN.00730116.