Cardiovascular Disease — 7

The ANGPTL3 directed (zodasiran) and APOC3 targeted drugs (plozasiran) are given once every three months, have a broad beneficial effect for multiple lipids, and may prove to be especially useful in people with mixed lipid abnormalities.

The relationship between HDL, often referred to as the “good cholesterol,” and cardiovascular outcomes is much different from LDL and triglycerides. HDL cholesterol is generally regarded as a bystander, not a driver of atherosclerosis. Paradoxically, very high levels of HDL, above 80 mg/dL, may carry a higher risk of all-cause or cardiovascular death. Not so “good” after all, these high levels are often associated with dysfunctional HDLs that don’t act in their scavenger role of cholesterol as expected. Like high triglyceride management, low HDL levels (<40 mg/dL in men, <50 mg/dL in women) typically respond to the same lifestyle alterations. In contrast to the large body of evidence of lowering LDL cholesterol, active efforts for modifying triglycerides or HDL cholesterol from clinical trials have less correlation or proof of improving cardiovascular outcomes. Still, what your doctor calls good lipid panel results are good.

Another vexing lipoprotein that has long been without a treatment, but with clear-cut risk, is lipoprotein(a) or Lp(a). Less than 0.5 percent of people undergo Lp(a) testing even though high levels constitute a risk factor for heart disease. Recently, a pill has been demonstrated to lower Lp(a) by 65 percent, but this is in early human trials, and, although likely, we don’t know for certain it will lower the risk of coronary atherosclerotic disease. There are also several ongoing efforts for small molecule drugs and biologics (small interfering RNAs) that are targeting Lp(a). It would not be surprising that if one of the drugs to lower Lp(a) in the future works, then its assay will be added to one’s routine lipid panel.

Many other lipid markers could be assessed that aren’t currently, but one that should be is Apolipoprotein B (apoB). While it typically correlates with LDL cholesterol, many impressive studies indicate it is a more accurate predictor of risk. About 20 percent of people who have a normal LDL cholesterol will have a high apoB, denoting risk of cardiovascular disease. That makes sense, because it is a more direct measurement—it is apoB that carries cholesterol in our blood. This protein encapsulates LDL particles but also intermediate-density lipoproteins (IDL), very low-density lipoproteins (VLDL), and Lp(a). Some people have a high apoB level but normal LDL cholesterol and are at high cardiovascular risk, which is why it’s an important lab test for people at risk to get, such as with metabolic syndrome, high triglycerides, or high polygenic risk score. It should be in the standard lipid panel, covered by insurance, but it usually isn’t. It’s worth getting at least once, or on occasion with routine lipid panels, to see if there is a divergence between one’s LDL cholesterol and apoB levels, and help monitor one’s level of risk, such as needing to increase a dose or potency of a statin medication. Perhaps someday its glaring omission, defying such a strong evidence base, will be fixed, and apoB will be part of standard panels. In the meantime, a proxy for apoB is to determine the non-HDL cholesterol by calculating total cholesterol minus HDL cholesterol. While not as good as a direct apoB measurement, that can usually be derived from routine lipid panels and correlates rather well.