Letter From the LipidSpin Editor: Cholesterol Limbo — How Low Can You Go?

The greater danger for most of us lies not in setting our aim too high and falling short; but in setting our aim too low, and achieving our mark.” Michelangelo Buonarroti

Along with the NLA Scientific Sessions, the summer also brings the anticipation of the Prescription Drug User Fee Act (PDUFA) dates for two new monoclonal antibody inhibitors for proprotein convertase subtilisin/ kexin type 9 (PCSK9). Data to date with this new class of medication for LDL lowering has shown dramatic reductions with minimal safety signals. Early data published in the New England Journal of Medicine (NEJM) shows statistically significant reductions in short- term safety trials for both of these products in cardiovascular events.1,2 The remaining safety analysis of these  agents has been similar to placebo.

Patients treated with PCSK9 inhibitors (PCSK9i) in clinical trials encompass many different patient groups. Some have extremely high entry LDL-C levels in the setting of familial hypercholesterolemia, while others remain at high risk despite optimal lipid management, and obtain very low LDL-C levels.  The lingering concern for these patients is the potential harm of achieving very low LDL cholesterol levels. Two recent studies however seem to minimize these risks. At the American College of Cardiology meeting this past March in San Diego, data was presented examining the safety data of patients treated with the PCSK9i Alirocumab obtaining LDL-C levels  either <25 mg/dL or < 15 mg/dL.3 Fourteen different trials were analyzed evaluating 796 patients <25 mg/dL and 288 patients <15 mg/dL. No safety signals were observed. Concern for low achieved LDL-C on treatment has been a concern since the data from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial published in 2006 showed a small increase in hemorrhagic stroke in those patients recent stroke or TIA treated with high dose atorvastatin.4 Data published online in April in Circulation evaluates the risk of intracranial hemorrhage (ICH) from statin use in Asian patients.5 This nationwide cohort study showed no observed association between cumulative statin use and risk of ICH among subjects without a prior history of stroke. There was a signal toward increased risk in those with no history of hypertension, however, which remains to be explained.

Ultimately, naturally occurring or obtained low LDL levels with lipid lowering therapy do not seem to be associated with increased safety concerns. While the ACC/AHA Guidelines on the Treatment of Blood Cholesterol suggest that for those patients who achieve LDL-C levels <40 mg/dL lipid lowering therapy should be removed, there is no scientific basis for this recommendation.6 In a recent article in the Lancet, Paul Ridker, MD, reviews the data regarding LDL and genetics. These data consistently support low LDL syndromes as having cardio-protective benefits.7 More recent data showing that mutations associated with the NPC1L1 receptor translate to a lifetime reduction in 12 mg/dL in LDL-C and translate to a >50 percent reduction in cardiovascular events.8 Low levels of LDL from  birth seem to be desirable and safe.

In summary, we are entering a new era of low LDL levels in our effort to prevent and treat cardiovascular risk. While the landscape is new and challenging, the roadmap seems to be one well worth following.