We first confirmed that elevated LDL-C levels were a risk factor for CVD and all-cause mortality in Chinese individuals ≥ 75 years old, and the increased risk of CVD caused by high LDL-C levels was mainly seen in acute myocardial infarction, without an increase in the risk of stroke; moreover, the risk of haemorrhagic stroke and ischaemic stroke did not increase.
A total of 3674 patients aged ≥ 75 years in the Kailuan study were followed up for nearly 10 years. After possible confounding factors were adjusted, it was found that the risks of CVD and acute myocardial infarction events in the LDL-C elevated group were 1.46 times and 2.08 times that of the ideal group. The risk of all-cause mortality was 1.12 times and 1.17 times that of the ideal group. There may be a dose-response relationship between LDL-C and the risk of CVD and all-cause mortality. For every SD (0.93 mmol/l) increase in LDL-C, the risk of CVD increased by 10%, the risk of acute myocardial infarction increased by 21% and the risk of death increased by 4%. The above-mentioned associations still existed after the onset of CVD was adjusted for the competing risk of death.
The association between elevated LDL-C and CVD in the adult population has been confirmed,11,12 but there is still controversy in the elderly population ≥ 75 years old. The findings from the National Institutes of Health pooled cohort indicated that elevated LDL-C levels have nothing to do with the risk of CVD in the elderly population ≥ 75.13 The results of a primary prevention cohort study in a 70 to 100 years old population showed that an elevated LDL-C level was associated with the risk of acute myocardial infarction and CVD. Every 1.0 mmol/L increase in the LDL-C level increased the risk of acute myocardial infarction and CVD by 25% and 12%, respectively.14 This study obtained similar results. For every increase in the LDL-C level (0.93 mmol/l), the risk of acute myocardial infarction and CVD increased by 21% and 10%, respectively. Our results show that high LDL-C is not a risk factor for stroke. A recent Korean national longitudinal study showed that a high LDL-C level is a protective factor against ischaemic stroke among individuals ≥ 65 years of age. The results showed that compared with those in the first quartile, the risk of ischaemic stroke for subjects in the fourth quartile of LDL-C was reduced by 20%.15
The relationship between LDL-C in the elderly and all-cause mortality is also controversial. The results of clinical studies in a 75-year-old population by Nilsson et al. showed that there was no correlation between LDL-C and all-cause mortality,16 while a study on the relationship between lipoprotein cholesterol levels and mortality found that there was a negative correlation between LDL-C and all-cause mortality in an elderly population ≥ 70 years old.17 However, a number of current interventional trials of lipid-lowering drugs have confirmed that LDL-C-lowering therapy in elderly individuals ≥ 75 years old significantly reduces the risk of cardiovascular death or all-cause mortality.18–23 Our results are consistent with the results of the intervention study.
Among our observation subjects, the average LDL-C level of the appropriate level group was 2.87 mmol/l, which was higher than the target LDL-C value of 2.6 mmol/l for primary prevention, but the CVD risk in the appropriate level group did not increase, while the risk of death increased by only 12% (P = 0.045). Therefore, a target value of 2.6 mmol/l for primary prevention among elderly patients may not be appropriate. According to our research, the target value can increase to 3.4 mmol/l.
Old age is an unchangeable risk factor, and elderly individuals often have multiple diseases. Therefore, randomized controlled trials often exclude elderly individuals. Even if elderly subjects are included, many conditions are set, and the results are not universal. The results of this research are derived from real-world data, so it has the value of promotion. Based on our research results, we support some guidelines, such as the 2018 Guideline for U.S. Blood Lipid Management11 and the 2019 Guideline for the Management of Dyslipidaemia in European Society of Cardiology/European Atherosclerosis Association,24 which are recommended for longer life expectancy (more than 1 year) and recommend that elderly patients ≥ 75 years old with elevated LDL-C levels should be given lipid-lowering treatment.
In our observation population, the risk of myocardial infarction was similar to all-cause mortality caused by high LDL-C levels, but the absolute number of all-cause deaths was much greater than the number of myocardial infarctions. Therefore, the greatest benefit of lipid-lowering intervention may be to reduce all-cause mortality. A study on the use of statins and all-cause mortality among veterans aged 75 years and over in the United States showed that the risk of all-cause mortality was reduced by 25% in those who took statins compared with those who did not take statins.25 Moreover, moderate-intensity statin treatment can reduce LDL-C levels by 25%-50%.9 According to this rough calculation, if the elevated group used statin drugs, LDL-C levels would drop to 1.94–2.91 mmol/l, which is close to the appropriate level. Therefore, adverse events, especially all-cause mortality, will be reduced.
Our results may underestimate the impact of high LDL-C levels on CVD and all-cause mortality in elderly people due to the deviation of healthy survival. Previous studies have found that exposure to high LDL-C levels at a young age is the main cause of early-onset CVD and early death. The average age in our observation population was 79 years old. These surviving individuals were relatively healthy compared to those with early-onset CVD or early death, and even the elevated LDL-C level was only 3.88 mmol/l,which was relatively small compared with the marginal increase of 3.4mmol/l in the primary prevention population of CVD in China, so we cannot observe the effect of higher LDL-C levels on CVD and all-cause mortality in the elderly populations, and this may underestimate the impact of LDL-C on CVD and all-cause mortality in elderly people.
Strengths and limitations of the study
Advantages of research: our data are from a relatively large and stable cohort. The penetration rate of statins in China was not high in 2006, and this study was not affected by the use of lipid-lowering drugs.
Our research also has certain limitations. There is no cause of death provided in the data. The subjects of observation are retirees who enjoy public medical care, so it may not be applicable to other groups of people. The observation subjects have a high proportion of males. Point estimation of LDL-C was carried out, and the influence of LDL-C levels changes on CVD and all-cause mortality was not observed.