VESL Wall, Issue #1, March 2021
Issue #1, March 2021

Welcome to the inaugural edition of the VESL Wall. Each month we will feature a few articles recently posted in the VESL community and highlight their clinical impact and Canadian perspective.
 

View a video summary of this issue of the VESL Wall with Dr. Liam Brunham >> Video Summary VESL Wall Issue #1 [8 min]
 
 
This month, we are featuring three new publications examining LDL-C lowering strategies in high-risk populations.

Are very low levels of LDL-C beneficial and safe?

The Canadian Cardiovascular Society (CCS) dyslipidemia guidelines, published in 2016, recommend a treat-to-target approach4. Several studies have now reported that layering PCSK9 inhibitors onto statin and/or ezetimibe therapy can result in significant numbers of patients achieving very low LDL-C levels (typically defined as below 30mg/dL, or 0.78 mmol/L). Karagiannis et al provide an updated review of the available evidence regarding the risks and benefits of achieving very low LDL-C. Sub-analyses appear to demonstrate cardiovascular clinical benefit is log linearly dependent on LDL-C, increases with lower LDL-C, and is seen even in patients with baseline LDL-C < 70 mg/dL (1.8 mg/dL). The benefit is similar no matter what therapeutic combination is used to achieve the very low LDL-C.

The authors also review the safety of achieving very low LDL-C levels, including neurocognitive, endocrine, and other body systems. Numerically higher rates of new onset diabetes and hemorrhagic stroke were observed in some studies, however no significant association has been seen. The authors conclude that the potential benefit and short-term safety profile of very low LDL-C levels suggest an advantage in specific high-risk patients. Additional studies are needed to compare the efficacy and safety of attaining very low LDL-C levels vs. current recommended targets1.

Does lipid-lowering therapy improve cardiovascular outcomes in FH patients?

Patients with familial hypercholesterolemia (FH) have elevated LDL-C levels from birth and are at markedly increased risk of atherosclerotic cardiovascular disease, so strategies to lower LDL-C are needed in these patients5. Vallejo-Vaj and colleagues wanted to understand, using data from the 4S secondary prevention outcomes study, if simvastatin therapy lowers the risk of cardiovascular outcomes in patients with an FH phenotype.

Participants were divided into cohorts according to LDL-C at baseline, premature coronary artery disease (CAD) and a sibling history of CAD. The FH phenotype group constituted 3.45% of the overall trial population, consistent with prevalence estimates of FH in the CAD population.

Although similar reductions in LDL-C were observed across cohorts, those with the FH phenotype appeared to derive the most benefit in clinical outcomes from simvastatin therapy, including:
  • 6.6% absolute risk reduction in all-cause death, compared with 3.8% reduction in the group with higher LDL-C and no other features of FH.
  • 13.2% absolute risk reduction in major coronary events, compared with an 8.3% reduction in the group with higher LDL-C and no other features of FH.
  • The trends for relative risk reduction were similar to the absolute risk reduction observations, demonstrating consistent, but non-significant additional benefit for FH phenotype patients.
These data suggest that patients with the FH phenotype derive even greater clinical benefit from lipid-lowering therapy than patients with similar LDL-C levels but without other features suggestive of FH2.

How can lipids be lowered in pediatric FH patients?

Kinnear and colleagues report on a small pilot designed to evaluate the feasibility of using validated behavioural interventions to improve diet and physical activity of families with a child aged 10-18 years diagnosed with FH. Dieticians delivered a single face-to-face intervention at baseline and followed up with four email or telephone sessions over a 12-week period. The pilot appeared feasible with participants feeling positive about the intervention. The data on behavior change is descriptive only but suggests more improvements were achieved in diet than physical activity. Nevertheless, lipid profiles appeared to improve over the course of the 12 weeks. As FH patients rarely achieve target lipid profiles with pharmacologic intervention alone, and as reviewed above, that there is no LDL-C concentration below which CVD risk ceases to improve, any additional LDL-C reduction that can be achieved through non-pharmacologic methods is welcome3. Canadian practitioners are reminded that the CCS states that lifestyle modification alone does not provided sufficient LDL-C reduction in children with FH, and statin therapy is recommended5. 77% of the children in the pilot study were taking statins3.

Summary

These new publications support the goal of lowering LDL-C to improve cardiovascular outcomes in patients with dyslipidemia. FH patients appear to derive increased benefit from lipid-lowering therapy, and it may be possible to layer targeted, behavioral interventions onto recommended statin therapy in pediatric FH patients.

Featured publications:

1. [PubMed Link] Karagiannis AD, Mehta A, Dhindsa DS, et al. How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol [published online ahead of print, 2021 Jan 19]. Eur Heart J. 2021;ehaa1080. doi:10.1093/eurheartj/ehaa1080

2. [PubMed Link] Vallejo-Vaz AJ, Packard CJ, Ference BA, et al. LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial [published online ahead of print, 2021 Jan 12]. Atherosclerosis. 2021;320:1-9. doi:10.1016/j.atherosclerosis.2021.01.003

3. [PubMed Link] Kinnear FJ, Lithander FE, Searle A, et al. Reducing cardiovascular disease risk among families with familial hypercholesterolaemia by improving diet and physical activity: a randomised controlled feasibility trial. BMJ Open. 2020;10(12):e044200. Published 2020 Dec 28. doi:10.1136/bmjopen-2020-044200

Additional reading:

4. [PubMed Link] Anderson TJ, Grégoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016;32(11):1263-1282. doi:10.1016/j.cjca.2016.07.510

5. [PubMed Link] Brunham LR, Ruel I, Aljenedil S, et al. Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018. Can J Cardiol. 2018;34(12):1553-1563. doi:10.1016/j.cjca.2018.09.005
 

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