Low-Density Lipoprotein Cholesterol: Lower Is Totally Better

Christopher P. Cannon, MD


J Am Coll Cardiol. 2020;75(17):2119-2121. 

Lowering low-density lipoprotein cholesterol (LDL-C) reduces morbidity and mortality in those with or at risk of cardiovascular (CV) disease.[1] The Cholesterol Treatment Trialists Collaboration (CTT) found that both a reduction in LDL-C of 1 mmol (39 mg/dl) leads to a 22% reduction in CV events.[1] They also noted that the greater the amount of LDL-C reduction, the greater the relative reduction in events.[1] Furthermore, as seen in the Heart Protection Study[2] and the CTT collaboration,[1] benefit was seen in each tertile of baseline LDL-C, meaning that no matter what LDL-C you start with, lowering LDL-C provides further CV benefit. This began discussion of the concept of "lower is better."

This hypothesis was directly tested in several trials, including the PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and TNT (Treat to New Target) trials, where high-dose statin was compared with standard-dose statin.[3,4] Indeed, the main objectives of PROVE IT were "to compare pravastatin with atorvastatin with the goal of determining whether lowering low-density lipoprotein (LDL) cholesterol with pravastatin to a level of approximately 100 mg/dl provides a clinical benefit similar to LDL cholesterol lowering with atorvastatin to a much lower level of approximately 70 mg/dl".[5] The results found that the more intensive lowering of LDL-C significantly reduced CV events.[3] This was confirmed in TNT[4] and 4 other trials. These trials all thus provide direct evidence supporting the "lower is better" concept.

In 2004, just months after publication of PROVE IT, the National Cholesterol Education Program Adult Treatment Panel III Guideline committee issued an update and noted that a new target LDL-C of <70 mg/dl was recommended for patients at very high risk.[6] This was the prevailing guideline approach for the next decade. However, this was challenged in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines;[7] the committee was charged with trying to be fully evidence based, and that committee noted that the exact implementation of this treat-to-target strategy (i.e., titration of dose of statin or addition of nonstatin agents) had not been as specifically tested in a strategy trial. As such, that guideline emphasized the use of intensive statin therapy for patients at higher risk. Of note, there actually had been 1 such trial published in 2004, the ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) trial, that did test the strategy of using atorvastatin titrated to LDL-C goals of <80 mg/dl versus usual care; the trial found a significant 17% reduction of CV events (p = 0.02).[8] This was one of the first pragmatic trials, which had less strict adherence to the protocol than more standard double-blind clinical trials and was thus not accepted quite as broadly.

Subsequently, IMPROVE IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) found that even greater reduction in LDL-C (to 54 mg/dl on average) with the addition of ezetimibe to statin therapy showed a significant reduction in CV events compared with statin therapy alone (with an achieved LDL-C of 69.5 mg/dl).[9] This trial advanced the "lower is better" concept—showing that even lower was even better.

The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor trials continued the push to lower and lower LDL-C levels, with average LDL-C levels achieved of 30 to 40 mg/dl in the 2 large outcomes trials with each showing significant further reduction in CV events.[10,11] Furthermore, an analysis by Giugliano et al.[12] looked at achieved LDL-C versus major adverse cardiac events and found it to be a linear reduction all the way down to 0! There were more than 500 patients with an achieved LDL-C <10 mg/dl, and their event rate was the lowest compared with patients of any greater level. This could lead one to say that "Lowest is best."

For the clinical question of titrating therapies to a specific goal, we have a prospectively designed Treat Stroke to Target trial. This study randomly assigned 2,860 patients with a recent stroke or transient ischemic attack (TIA) to strategies of titrating statin (and ezetimibe) therapy to a goal of <100 mg/dl versus a goal of <70 mg/dl. They showed a significant 22% reduction in recurrent events with titration to the lower goal.[13] This fully solidifies the evidence base supporting the titration of LDL-C lowering therapies to a low target.

However, the benefits of LDL-C lowering are even greater: beginning with the TNT and IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trials, analyses of not just the first event, but also counting recurrent events, found additional benefit of intensive LDL-C lowering.[14,15] In these 2 trials, intensive statin therapy not only significantly reduced the first event, but also the second event, and the third, fourth, and fifth! Analysis of the total number of events found that there were about twice as many total events prevented than when counting only the first. The same was true in the PROVE IT trial,[16] and then also in the IMPROVE IT trial with ezetimibe,[17] and then also in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) with PCSK9 inhibitors.[18,19] Most recently, REDUCE IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) also found further CV benefit on total events with the addition of icosapent ethyl.[20] These analyses show that with roughly twice the number of total events prevented, the number of patients needed to prevent 1 event is approximately one-half that of the main trial analysis. This leads to a better cost/benefit ratio.

In this issue of the Journal, the latest analysis of total events comes from the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial of atorvastatin versus placebo in 4,731 patients with recent stroke or transient ischemic attack and no known coronary heart disease.[21] The LDL-C values were reduced from 132 mg/dl at baseline to 58 mg/dl in the atorvastatin group. The main trial found a significant 16% reduction in first fatal or nonfatal stroke (p = 0.03) and a 20% reduction in first major CV events (p = 0.002).[22] The current analysis found that there were 164 fewer first events and a total of 390 fewer total vascular events in the atorvastatin group—a highly significant 20% reduction in total events.[21] This included 177 fewer cerebrovascular, 170 fewer coronary, and 43 fewer peripheral vascular events, corresponding to reductions in total cerebrovascular events by 24% (p < 0.001), total coronary events by 46% (p < 0.001), and total peripheral vascular events by 44% (p = 0.014). Thus, as seen in the coronary artery disease trials, when considering total vascular events, there are more than twice as many total events prevented.

With this expansive evidence base, the 2018 ACC/AHA guidelines now note, "This confirms the general principle that 'lower is better' for LDL-C".[23] The 2019 European Society of Cardiology guidelines highlighted the first key message: "Throughout the range of LDL-C levels, 'lower is better' with no lower threshold, at least down to <1 mmol/L" (39 mg/dl).[24] With this newest analysis,[21] one could now say, "lower is totally better!"