Guest Editorial: Clinicians Should Monitor LDL-C After Starting Lipid-Lowering Therapy

Multiple randomized controlled trials have demonstrated significant reductions in major cardiovascular (CV) events and mortality with statin therapy.(1) These data have supported the “LDL-C treatment strategy,” in which CV event risk reduction is directly proportionate to the extent of LDL-C lowering.(2) Because the majority of these trials studied fixed-dose statin regimens, this approach became the foundation of initial treatment recommendations within the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.(3)

The hallmark of the 2013 guideline was the removal of recommendations for specified LDL-C treatment goals. Instead, clinicians were recommended to implement a fixed-intensity statin regimen based on a patient’s respective atherosclerotic cardiovascular disease (ASCVD) risk. Additionally, follow-up lipid panels were recommended as a strategy to assure medication adherence and achievement of an expected LDL-C lowering response, and not as a guide to titrate therapy like prior guidelines have recommended.

Fast forward five years. 2018 AHA/ ACC Multisociety Guideline on the Management of Blood Cholesterol reintroduces the recommendation to monitor LDL-C levels to assess achievement of a goal percentage of LDL-C reduction from baseline.(4) Moreover, this guideline also includes LDL-C thresholds for patients with clinical ASCVD or severe primary hypercholesterolemia (baseline LDL-C ≥190 mg/dL) as a trigger for the clinician to intensify statin therapy or add non-statin lipid lowering agents for further LDL-C reduction. The bottom line is that compared to 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, the 2018 AHA/ACC Multisociety Guideline on the Management of Blood Cholesterol places greater emphasis and importance on measuring a follow-up lipid panel for patients newly started on statin therapy, which better endorses evidencedbased practice.

There are various reasons why patients may not have an expected reduction in LDL-C when started on statin therapy, or other non-statin LDL-C lowering therapy. These may include nonadherence, presence of adverse effects that alter medication adherence patterns, or possible interpatient variability. In clinical trials, these potential reasons for failing to achieve reductions in LDL-C are less prominent as adherence is rigorously evaluated and facilitated by study investigators. Additionally, patients likely to experience adverse effects are often not included, or when adverse effects occur, they are managed using proactive and timely strategies. This is very challenging, if not impossible, to replicate within the clinical environment. Therefore, the most logical way to mimic trial interventions in an effort to reproduce CV event reduction benefits, is by not just simply using the drug regimens chosen, but also by achieving the percent LDL-C reductions that were demonstrated. The only way to do this is through ongoing LDL-C monitoring. 

The 2018 AHA/ACC/Multisociety guideline recommends that the effects of LDL-C lowering therapy should be assessed by measuring a fasting lipid panel 4-12 weeks after statin initiation or dose adjustment, and then every 3 to 12 months thereafter.(4) This Class 1, Level of Evidence A recommendation is crucial to ensure patients are sufficiently treated in a timely manner, as sub-therapeutic statin therapy has been associated with negative outcomes. For example, a 2019 prospective cohort study in the United Kingdom demonstrated that 51.2% of patients (n=84,609) without previous CV disease had a suboptimal LDL-C response (<40% reduction) within 24 months of newly initiated statin therapy.(5) When comparing the incidence of CV disease, suboptimal responders were 22% more likely to develop CV disease compared to those who responded optimally (HR 1.22 [95% CI 1.19 to 1.25]). Similarly, a retrospective study that investigated LDL-C management of 281,665 adult patients with clinical ASCVD found that 36.6% of patients did not achieve goal LDL-C levels < 2.0 mmol/L (77 mg/dL) or at least a 50% LDL-C reduction at follow-up compared to the first LDL-C measured during the study period.(6)

We have evaluated if there has been an increase in LDL-C measurement incidences as a result of 2018 guideline monitoring recommendations at the University of Colorado Health System in patients newly started on statin therapy. Our retrospective study design compared the incidence of LDL-C measurements 4 to 12 weeks after initiation of statin therapy in patients started on a statin pre2018 guideline release (n=7,476) with patients started on a statin after the 2018 guideline (n=6,250). The percentage of patients with a lipid panel measured was 13.9% in the pre-2018 guideline cohort and increased to 16.2% in the post-2018 guideline cohort (P <0.001). While statistically significant, this meager 2.3% increase in monitoring is unacceptable. Without ascertaining the extent of LDL-C lowering after starting therapy, patients cannot be provided the most optimal riskreducing lipid-lowering regimen.

As Lipid Specialists, we need to treat our patients in a manner that maximizes cardiovascular risk reduction and follows the evidence. While it is not the only important aspect, clinical care of the patient with hypercholesterolemia starts with simple foundational steps, and measuring LDL-C lowering after implementing therapy needs to be included. Lipid Specialists also have the opportunity to educate other colleagues who treat cardiovascular risk to provide care this same way.

Summary
Reduction in CV events with lipid-lowering drug therapy are directly proportionate to the extent of LDL-C lowering. Clinicians should routinely measure fasting LDL-C after starting lipid-lowering drug therapy to assure response is sufficient and maximize long-term benefits. 

Disclosure statement:
Dr. Tunoa has no financial disclosures to report. Dr. Saseen has no financial disclosures to report.

References:
1. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532- 61.
2. Cholesterol Treatment Trialists Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a metaanalysis. Lancet 2008;371:117-25.
3. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1-45.
4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-e143.
5. Akyea RK, Kai J, Qureshi N, Iyen B, Weng SF. LDL cholesterol response to statins and future risk of cardiovascular disease. Heart 2019;105:1290-1.
6. Chen G, Farris MS, Cowling T, et al. Treatment and Low-Density Lipoprotein Cholesterol Management in Patients Diagnosed With Clinical Atherosclerotic Cardiovascular Disease in Alberta. Can J Cardiol 2019;35:884-91.