Treatment of Blood Cholesterol for Atherosclerotic Cardiovascular Disease Risk Reduction – An Evolving Landscape that treating LDL-C to levels well below guideline-recommended goals to ranges of 30-50mg/dL may continue to confer additional cardioprotective benefits. However, the safety of reaching and maintaining such low levels of LDL-C has become an increasingly important topic of discussion. Cholesterol is essential to basic cellular membrane integrity, and plays an essential role in adrenocortical and hepatobiliary function.28 Earlier observational studies and some findings from clinical trials have raised concerns that low serum cholesterol levels were associated with disruption in production of steroid based hormones and absorption of fat-soluble vitamins, in addition to increased rates of adverse events. For instance, previous findings of a U-shape relationship in total mortality with respect to total cholesterol levels link low ranges of total cholesterol with higher rates of non-cardiovascular deaths.29 Some previous studies on statins have reported association between treatment to low LDL-C levels and increased risk of cancers, and hemorrhagic strokes.30,31 Post-hoc analysis from the JUPITER trial also found association between low LDL-C (<30mg/dL) with diabetes with some subsequent metaanalysis also showing increased association with higher intensity statin regimens with diabetes.32,33 Some evidence of cognitive decline was also observed in earlier studies involving treatment with PCSK9 inhibitors.34 With respect to cancers and hemorrhagic strokes, new data—especially from more recent, larger outcomes trials—do not appear to support association between treatment lowered LDL-C thresholds with adverse events. Randomized control data including meta-analysis from the Cholesterol Treatment Trialists’ (CTT) Collaboration did not find significant differences in cancer incidence, mortality, or any non-vascular mortality in statin compared with control groups.4 Furthermore, longitudinal safety data from IMPROVE-IT, FOURIER and ODDYSSEY OUTCOMES trials did not show any significant differences in major adverse events including incidence of diabetes, hemorrhagic strokes, neurocognitive decline or cancers.5-7,35,36 There were also no differences in levels of fat soluble vitamins and steroid hormone levels detected between the treatment and control arms. In pooled analysis of trials involving alirocumab, very low achieved levels of LDL-C were associated with more cataracts.36 With regards to diabetes, it is unclear whether the association is with statins or with achieving very low LDL-C levels. Again, studies of ezetimibe and PCSK9 inhibitors did not demonstrate increased incidence of diabetes despite low LDL-C levels achieved, although the majority of patients included in FOURIER and ODDYSSEY OUTCOMES were also on high intensity statins at baseline. Taken as a whole, the benefit of
lowering LDL-C and reducing ASCVD risk, especially in high risk patient groups, likely outweighs the possibility for incident diabetes. Thus, treatment to LDL-C ranges of 30-50mg/dL likely confers a net benefit, from cardiovascular risk reduction. As such, the 2018 guideline recommends using clinical judgement regarding whether to de-intensify LDL-C lowering therapy in the setting of two repeat labs showing LDL-C levels <25mg/dL. Therapies on the Horizon Continuing research into new therapies targeting LDL-C have the potential to provide clinicians with additional tools in preventing ASCVD events. Two new agents in the developmental pipeline to note are inclisiran and bempedoic acid. Inclisiran is a small interfering RNA (siRNA) molecule, administered as subcutaneous injections, against PCSK9.37 In a phase 2 trial, inclisiran was shown to significantly reduce PCKS9 and LDL-C levels in a dose-dependent manner, with effects on lipid profile persisting over 6 months even after single dose.38 The long half-life of inclisiran has the potential to allow for drug administration every several months, which may improve ease of use as well as adherence compared to current PCSK9 mAb agents, which requires either once or twice per month administration. However, the pharmacodynamics features can also lead to longer duration of side effects, should they develop. The most common adverse effects observed were musculoskeletal pain, headache, nasopharyngeal symptoms, dizziness, fatigue, hypertension and diarrhea. Serious adverse events were not significantly different between treatment and placebo groups in previous trials (Ray NEJM 2017). Several phase 3 clinical trials (ORION-9, 10, 11) (ClinicalTrials.gov Identifier: NCT03397121; ClinicalTrials.gov Identifier: NCT03399370; ClinicalTrials.gov Identifier: NCT03400800), including a cardiovascular outcomes trial (ORION-4) (ClinicalTrials.gov Identifier: NCT03705234) are underway. Bempedoic acid, on the other hand, is an oral agent that targets the adenosine triphosphate (ATP) citrate lyase (ACL): an enzyme within the cholesterol synthesis pathway upstream of HMG-CoA reductase. Several clinical trials have shown safety and efficacy of bempedoic acid in patients with elevated LDL-C. Bempedoic acid was shown to reduce LDL-C in a dose dependent fashion up to 26.6% in hypercholesterolemia patients with or without elevated triglycerides.39 In a study of patients with hypercholesterolemia and diabetes, the group on bempedoic acid had a significant reduction of LDL-C by 39% and non-high-density-lipoprotein cholesterol (nonHDL-C) by 31.4% compared to placebo.40 Meanwhile, the combination bempedoic acid with ezetimibe was shown in the phase 3 CLEAR-Tranquility trial to reduce LDL-C by 28.5% when compared with ezetimibe alone, which may represent a beneficial therapeutic
option for patients who cannot tolerate statin therapy.41 Several ongoing phase 3 clinical trials involving bempedoic acid include an outcome trial: CLEAR Outcomes (ClinicalTrials.gov Identifier: NCT02993406). Conclusion Although LDL-C and non-HDL-C are well-established risk factors for ASCVD, nuances in treatment of serum cholesterol have continued to evolve. Growing evidence suggests that treatment of LDL-C and nonHDL-C to lower targets may confer additional ASCVD risk reduction, especially in high risk patients. And while statins remain the first line therapy for LDL-C reduction, ezetimibe and PCSK9 inhibitors provide additional, evidence-based options when additional therapies are needed to achieve cholesterol targets, or when patients have significant statin-associated side effects. Moreover, newer therapies are in development that will further expand the horizon for LDL-C treatment. Xiaoming Jia, MD is a Lipid and Atherosclerosis Fellow at the Baylor College of Medicine in Houston, TX
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