Remember when we used to tell patients that high-density lipoprotein cholesterol (HDL-C) was “healthy” of the “highly desirable lipoprotein”? Well, a number of research studies in recent years have caused cardiovascular and lipid experts to say that the information obtained about HDL via epidemiology led us in the wrong direction.
One pharmaceutical company lost almost a billion dollars when it’s trial of a cholesterol ester transfer protein (CETP) inhibitor more than doubled HDL-C but patients in the treatment group had a higher death rate, so the trial was halted early as raising HDL-C failed to provide benefit. Other clinical trials that used niacin, which significantly increases HDL-C but doesn’t significantly increase HDL particle number, failed to improve cardiovascular clinical outcomes. This in turn led authors of the American College of Cardiology (ACC) not to recommend niacin in the March 2016 clinical guidelines regarding the role of non-statin therapies in the management of cardiovascular risk.
A more recent study by Sharif and colleagues published in the May issue of Diabetes Care sought to find out if low HDL-C was a risk factor for cardiovascular disease and mortality in subjects with type 2 diabetes mellitus. They also wanted to find out if low HDL-C would remain a residual risk factor in those on intensive lipid-lowering therapy and/or if LDL-C goals were met.
Data was obtained from a cohort (n=1829) of subjects with diabetes enrolled in the Second Manifestations of ARTerial Disease (SMART) trial. LDL-C levels were stratified into three groups: <77 mg/dL, 77-97 mg/dL, and >97 mg/dL and the intensity of their lipid-lowering therapy. Adjustments were made relating to confounding variables such as BMI, gender, age, triglycerides, LDL-C, HbA1c, glucose, estimated glomerular filtration rate, alcohol, and smoking. During the (median) 7 years of follow-up, there were 335 new cardiovascular events and 385 deaths. The investigators found no relationship between HDL-C levels and cardiovascular events. In fact, in their conclusion they stated that they unexpectedly found that subjects with Diabetes and LDL-C levels <77 mg/dL and higher HDL-C at baseline had an increased risk of cardiovascular events and all-cause mortality.
So… gone are the days when we can simply say that HDL is “good”. Experts continue to marvel at the recent discoveries related to the complexity of the proteomics and lipidomics of HDL cholesterol. In order to prevent events, we need to move beyond HDL-C measurements. Research is currently underway to help us understand how HDL functions and how we can better identify those who are at a higher cardiovascular risk based on HDL functionality rather than on the amount of cholesterol found in the HDL particle.