Reduction of LDL Cholesterol in the Prevention of Cardiovascular Morbidity and Mortality – Results of a Large Meta-Analysis

Introduction

LDL cholesterol is one of the main risk factors for the development of atherosclerotic cardiovascular disease. The current European ESC/EAS recommendations from 2019 emphasize the crucial importance of individual CV risk (based on SCORE tables) for choosing and intensifying lipid-lowering therapy. The target LDL-c values according to current recommendations are as follows:

• < 3.0 mmol/l for patients with low risk
• < 2.6 mmol/l for patients with moderate risk
• < 1.8 mmol/l for patients with high risk
• < 1.4 mmol/l for patients in secondary prevention or with very high risk in primary prevention

At the same time, the goal should be to reduce the baseline LDL-c value by 50%. Any reduction in LDL-c achieved through therapy is beneficial. This is also evidenced by an analysis published in the journal Lancet Diabetes & Endocrinology.

Meta-Analysis

A total of 52 studies available as of June 15, 2019, in the Medline, Embase, and Cochrane databases were included in the meta-analysis. These were randomized controlled trials involving a total of 327,037 subjects, examining the efficacy and safety of lipid-lowering drugs (statins, ezetimibe, and PCSK9 inhibitors) used in monotherapy or combination for primary or secondary prevention. The aim was to assess the effect of reducing LDL-c levels on the risk of a major vascular event (CV death, nonfatal acute myocardial infarction, ischemic stroke, or need for coronary revascularization).

Findings

Each reduction of LDL-c by 1 mmol/l was associated with a 19% reduction in the relative risk (RR) of a major vascular event (RR 0.81; 95% confidence interval [CI] 0.78–0.84; p < 0.0001). A similar trend was observed in all subgroups of patients with baseline LDL-c values ≤ 2.6 mmol/l, 2.61–3.40 mmol/l, 3.41–4.10 mmol/l, and ≥ 4.11 mmol/l. There was no difference observed among the individual lipid-lowering drugs. For statins, RR was 0.79 (0.75–0.89), for ezetimibe 0.83 (0.78–0.89), and for PCSK9 inhibitors 0.85 (0.80–0.90; p < 0.0001 for all comparisons). In the subgroup of patients (n = 22,860) with LDL-c levels < 2.07 mmol/l, a 17% reduction in relative risk was observed (RR 0.83; 95% CI 0.75–0.92; p = 0.001).

A somewhat greater reduction in relative risk was noted in patients with lower 10-year CV risk (change in RR for every 10% 10-year CV risk 0.97; 95% CI 0.95–0.98; p < 0.0001) and individuals aged 50–75 (change in RR for every 10 years of age 0.92; 95% CI 0.83–0.97; p = 0.015).

There was no difference in RR reduction in patients based on the presence or absence of diabetes, chronic kidney disease (defined as estimated glomerular filtration rate < 1 ml/s per 1.73 m²), or gender. Patients without heart failure had a greater reduction in RR than those with the condition, but the difference was not statistically significant.

Statin use was associated with elevated aminotransferases (RR 1.67; 95% CI 1.35–2.05; p < 0.0001) and creatine kinase (RR 1.71; 95% CI 1.05–2.79; p = 0.031) in patients with more intensive lipid-lowering therapy. However, the annual rate of these adverse effects was only 0.28 and 0.12% per patient-year. The feared increased risk of myalgia, myopathy, and rhabdomyolysis was not apparent. Ezetimibe use was not associated with a significantly increased risk of adverse effects. In the case of PCSK9 inhibitors, injection site reactions were reported (RR 1.79; 1.24–2.59; p = 0.002 compared to placebo).

Conclusion

Each reduction of LDL-c by 1 mmol/l results in a reduced risk of a major CV event, regardless of baseline LDL-c value, gender, and the presence or absence of diabetes or chronic kidney disease. Patients with lower 10-year CV risk and younger individuals benefit from LDL-c reduction similarly to higher-risk and older patients.

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Sources:
1. 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 (1): 39–49, doi: 10.1016/S2213-8587(19)303088-2.
2. Češka R. et al. Interna (3rd, updated edition). Triton, Prague, 2020: 284.