Editor's Note: Commentary based on Brandts J, Ray KK. Low density lipoprotein cholesterol – lowering strategies and population health time to move to a cumulative exposure model. Circulation 2020;141:873–6.

We provide a brief synopsis of the recent article by Drs. Brandts and Ray, which challenges clinicians to move to an approach considering cumulative, time-varying exposure.

Cumulative exposure model:

• A cumulative exposure model approaches risk factor reduction with the intent of establishing a significant, durable reduction over time
• Smaller, sustained differences in low-density lipoprotein cholesterol (LDL-C) may provide similar benefits to larger, less sustained differences
• Annual time-averaged LDL-C per person per year accounts for adherence and dosing variability and, as a result, can improve assessment of long-term benefit of therapies on cardiovascular risk reduction

Barriers to a durable response with lipid lowering therapies:

• Patient-related factors [risk perception of an asymptomatic disease, i.e. atherosclerotic cardiovascular disease (ASCVD), health literacy, and medication adherence] impact optimal medical therapy effects
• Systems-related factors, such as complex access issues (including insurance, availability of refills, navigating formularies and cost) remain difficult to tackle
• Dosing intervals may impact medication adherence and, as a result, attenuate observed LDL-C reduction

Support for this model:

• Current therapies for LDL-C lowering shown to reduce cardiovascular risk include statins, ezetimibe, and monoclonal antibodies to PCSK9
• Promising therapies, but currently lacking cardiovascular outcomes data, include bempedoic acid and small interfering RNA therapeutics (siRNA), like inclisiran —bempedoic acid is newly FDA approved; inclisiran's approval is anticipated in the near future
• High-intensity statins and PCSK9 drugs typically result in a >50% LDL-C reduction
• Based on population modeling, an LDL-C reduction of 13 mg/dL over 50 years provides equivalent benefit to an LDL-C reduction of 39mg/dL over 5 years
• It is well established by the Cholesterol Treatment Trialists that for each 39 mg/dL reduction in LDL-C, clinicians and patients can expect a proportional risk reduction of 22% over 5 years
• Regimens that require more frequent dosing, such as statins, may be less likely to achieve their anticipated reduction as compared to regimens with fewer doses, such as PCSK9 inhibitors
• The authors hypothesize that an siRNA, administered twice yearly by physicians, would expect no loss of LDL-C lowering and thus can be considered to achieve full reduction in LDL-C 
• Based on an estimated attenuation of observed LDL-C reduction, for each expected 39 mg/dL decrease, statins may only reach a 13.5% risk reduction, PCSK9 inhibitors 17.5%, whereas perfect adherence options (potentially siRNAs or similar) may result in the full 22% risk reduction

Principal findings: Therapies that can improve long-term adherence and thus increase cumulative exposure to decreased LDL-C will likely be more efficacious in preserving population health assuming there are no side effects.

Perspectives:

• Dosing frequency is only one of the multitude of factors affecting adherence to therapy
• High-intensity statin therapy can lower LDL-C 50% and a 39 mg/dL reduction is a modest result that would be anticipated in a patient with an LDL-C of 78 mg/dL at baseline
• An absolute LDL-C lowering of 39 mg/dL can be far exceeded for those with baseline LDL-C >78 mg/dL, as the absolute lowering is a function of the percentage lowering applied to the baseline LDL-C
• The assumption of perfect adherence to newer therapies may be aspirational given barriers that the study's authors bring up, including but not limited to cost of these therapies, access to care, missed appointments and medical literacy
• Non-adherence is a fundamental clinical challenge requiring innovation and new approaches are welcomed
• A population-based approach that integrates both tried and tested modalities to lower cumulative exposure to LDL-C, as well as novel therapies with longer duration, could enable the field of Preventive Cardiology to make a greater impact in the health of our communities

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering, PCSK9 protein, human, Proprotein Convertase 9, Cardiovascular Diseases, Medication Adherence, Antibodies, Monoclonal, Health Literacy, Risk Factors, Cholesterol, Dicarboxylic Acids

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