Cardiovascular Disease — 6

It isn’t clear what is the optimal target level, but in people who have manifested coronary atherosclerotic disease, it would be reasonable to get below 50 mg/dL if the drug(s) is/are well tolerated. Some physicians have extrapolated from the data accrued that going ultra-low, as close to zero as possible, even in people with elevated LDL but otherwise healthy, without risk factors, should expand health span. There’s no hard evidence for that yet, but the trend in recent years has been more aggressive lowering and starting at as early an age as possible in people with elevated LDL and other cardiovascular risk factors. The results from further analysis of a recent trial in people with stable coronary artery disease indicated better protection for reduction of cardiovascular death, heart attack (MI), and stroke with LDL cholesterol lowered less than 20 mg/dL and reinforce this aggressive goal as a secondary prevention (fig. 5.5). I want to remind you of the increased risk of type 2 diabetes with the use of aggressive statin dosing, such as was seen in a randomized trial of rosuvastatin versus atorvastatin and an overview of all trials. On the other hand, there is evidence to support the benefit of statins and low risk in people aged eighty-five years and older.

Figure 5.4. Lowering of LDL cholesterol in various randomized trials and reduction of major cardiovascular events. Trial names are acronyms. Adapted from FB Mensink et al., “Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome,” Frontiers in Cardiovascular Medicine 9 (December 2022): 1061346, https://doi.org/10.3389/fcvm.2022.1061346.

There are other lipid assays, which are lab tests to find and measure a specific substance, associated with atherosclerosis. In the typical panel, triglycerides and HDL cholesterol are incorporated. As reviewed in the metabolic syndrome (chapter 1), high fasting triglycerides and low HDL are two of the main indicators of potential insulin resistance. There is a direct correlation between triglycerides and heightened risk. Unless extremely high, moderately elevated levels are usually responsive to weight loss and attention to the lifestyle+ factors. For people with high risk of heart disease and lack of response from changes in lifestyle, treatment with icosapent ethyl (Vascepa), a modified form of the fish oil called eicosapentanoic acid, may be useful. That treatment is backed up by a large randomized trial for protection against cardiovascular events, but the results remain controversial since other trials of fish oils have not been found to reduce adverse events. Olezarsen, an antisense drug being developed for high triglycerides, has been shown to be effective for a 50 percent reduction via a monthly injection. Marked lowering of triglycerides is now being achieved with RNA-interfering drugs directed against the angiopoietin-like 3 (ANPTL3) gene and the apoprotein C3 (APOC3) gene. People with two copies of the genes for familial hypercholesterolemia are at extremely high risk for atherosclerosis at a young age. That’s why it’s good that a monoclonal antibody to ANGPTL3, Evinacumab (Evkeeza), has been approved for the treatment of this rare disease in children.