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Featured commentary on early intervention & adherence
February 2020

The 2019 ESC/EAS guidelines recommend lower LDL cholesterol levels to optimise global cardiovascular risk reduction. A key practical deterrent, however, is adherence. This month’s commentary discusses new evidence for early intervention to optimise population health, together with novel approaches that may offer solutions to the issue of poor adherence.

Targeting LDL cholesterol: early treatment is key to population health

Lower LDL cholesterol is better’ is a key premise of the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS Guidelines for Dyslipidaemia).1 Low-density lipoprotein(LDL) is indisputably causal for atherosclerotic cardiovascular disease (ASCVD),2 and clinical data show no evidence of a threshold for clinical benefit from LDL-lowering.3,4 Indeed, it should be borne in mind that the LDL cholesterol goals in the ESC/EAS Guidelines are the maximum recommended levels for each global risk category, and that clinicians should aim for values below these wherever possible.

Given that atherosclerosis is a chronic inflammatory disease, it would make good clinical and economic sense to intervene against LDL cholesterol earlier, before the advent of subclinical disease. There has, however, been uncertainty regarding the clinical benefit derived at different baseline LDL cholesterol levels.  This question (amongst others) was the focus of a recent meta-analysis.5

In this report,5 investigators analysed data from 327,037 patients enrolled in 52 randomised controlled trials of cholesterol-lowering drugs, each with at least 1000 patient-years of follow-up. The primary cardiovascular endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, non-fatal ischaemic stroke, or coronary revascularisation. The therapeutic interventions included three mechanistically distinct classes—statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

The study demonstrated that irrespective of the type of therapy, each 1 mmol/L reduction in LDL cholesterol was associated with a 19% relative risk (RR) reduction in the primary cardiovascular endpoint (RR 0.81, 95% confidence interval [CI] 0.78–0.84). Results were similar across the three treatment classes (RR 0.79, 95% CI 0.75–0.82 for statins; 0.83, 95% CI 0.78–0.89 for ezetimibe; and 0.85, 95% CI 0.80–0.90 for PCSK9 inhibitors). Importantly, this cardiovascular benefit was also consistent across the range of starting LDL cholesterol levels (ranging from <2.07 mmol/L to >4.1 mmol/L), and independent of the presence of diabetes or chronic kidney disease. Additional analyses showed that there appeared to be greater benefit from LDL cholesterol lowering among individuals at lower ASCVD risk (change in RR per 10% lower 10-year ASCVD risk 0.97, 95% CI 0.95–0.98; p<0·0001) and those who were younger (change in RR per 10 years younger age 0.92, 95% CI 0.83–0.97; p=0·015). The investigators did, however, acknowledge that these analyses were exploratory rather than definitive.

Irrespective of the caveats associated with such exploratory analyses, the findings suggest that individuals at lower cardiovascular risk and younger age derive at least similar clinical benefit from LDL- cholesterol lowering. These data therefore provide a basis for considering earlier intervention in younger individuals at lower ASCVD risk. Such a strategy would make good theoretical sense, as starting LDL-lowering therapy early could slow the development and progression of atherosclerotic plaques when these are too small to initiate atherothrombotic complications, culminating in greater reduction in the long-term risk of cardiovascular events  than in older or higher risk individuals with more advanced ASCVD.2 Genetic studies also lend support, showing that lifelong exposure to lower LDL cholesterol levels due to carriage of variants in the PCSK9 gene or the gene encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the target of statins), confers a reduced risk of ASCVD events.6,7 Thus, a smaller decrease in LDL cholesterol, compared with relatively short-term treatment trials, from an earlier age would be expected to confer greater clinical benefit over the lifetime of the individual.

With chronic treatment, however, there are other issues. One key problem is long-term adherence,  a well-recognised issue in high- and very-high risk individuals, which detrimentally impacts clinical outcome and increases the risk of death.8-10 Among younger, lower-risk individuals, adherence problems may be even more important, as they may perceive no immediate benefit to treatment yet experience adverse side effects.

Against this scenario, could the concept of immunisation aiming to lower LDL cholesterol levels, while at the same time obviating the burden of adherence, be feasible? Experimental data lend support to this concept. For example, in a mouse model of atherosclerosis, administration of a peptide PCSK9 vaccine elicited anti-PCSK9 antibodies and reduced LDL cholesterol levels, with response sustained for up to 24 weeks.11 In a different rodent model, a nanoliposomal vaccine resulted in functional PCSK9-specific antibodies, with long-lasting lowering of LDL cholesterol levels by about 50%.12 Clinical data are, however, lacking. An alternative approach to sustained LDL cholesterol lowering – albeit not vaccination - is the application of small interfering RNA (siRNA) technology targeting hepatic PCSK9 production. Studies with the siRNA inclisiran have demonstrated durable LDL cholesterol lowering by about 50% when administered every 6 months in the clinic.13

However, for longer-lasting therapeutic benefit from only a single treatment, CRISPR-Cas9 genome editing may ‘fit the bill’. Until recently, the use of this approach in biomedical research has been hampered by the lack of a safe and effective in vivo delivery. The development of a non-viral delivery system using lipid-like nanoparticles looks promising in preclinical studies, providing controllable in vivo genome editing which is also highly specific to the liver.14 If proven to be safe, this strategy would be a key strategy to implementing successful early intervention, to improve the health of the population, and undoubtedly provide socioeconomic benefit by avoiding the costly complications of ASCVD.

References

  1. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41:111-88.
  2. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38:2459-72.
  3. Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA 2018; 319: 1566–79.
  4. Sabatine MS, Wiviott SD, Im K, et al. Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: a metaanalysis. JAMA Cardiol 2018; 3: 823–28.
  5. Wang N, Fulcher J, Abeysuriya N, et al. Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and meta-analysis of randomised trials including 327 037 participants. Lancet Diabetes Endocrinol 2020; 8:36-49.
  6. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012; 60: 2631–9.
  7. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016; 375:2144-53.
  8. Karlsson SA, Franzén S, Svensson AM, et al. Prescription of lipid-lowering medications for patients with type 2 diabetes mellitus and risk-associated LDL cholesterol: a nationwide study of guideline adherence from the Swedish National Diabetes Register. BMC Health Serv Res 2018;18(1):900.
  9. Lassenius MI, Toppila I, Bergius S, et al. Cardiovascular event rates increase after each recurrence and associate with poor statin adherence. Eur J Prev Cardiol 2020; doi: 10.1177/2047487320904334. [Epub ahead of print]
  10. Rodriguez F, Maron DJ, Knowles JW, et al. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2019; 4:206-13.
  11. Kawakami R, Nozato Y, Nakagami H, et al. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS One 2018;13(2): e0191895.
  12. Momtazi-Borojeni AA, Jaafari MR, Badiee A, et al. Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis. BMC Med 2019;17(1):223.
  13. Ray KK, Stoekenbroek RM, Kallend D, et al. Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial. JAMA Cardiol 2019; doi: 10.1001/jamacardio.2019.3502. [Epub ahead of print]
  14. Ding Q, Strong A, Patel KM, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014; 115:488-92.
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