The main finding of this cohort study is that LDL-C is a significant and independent predictor of all-cause mortality in community-dwelling adults. After adjustment for possible confounding factors, the results showed that participants with the lowest LDL-C levels (< 70 mg/dL) were at a significantly higher risk for all-cause mortality than those with high LDL-C levels (≥ 144 mg/dL). Participants who died within three years of the follow-up were excluded to avoid the possibility of reverse causality, although the results remain largely unchanged. Further, LDL-C levels were significantly associated with death among those aged 75 years or older. To the best of our knowledge, few studies have demonstrated the relationship between LDL-C level and all-cause mortality in Japanese community-dwelling persons.
The results of this study, especially that low LDL-C levels are significantly associated with an increased risk of all-cause mortality, are consistent with the results of several existing studies. The Kangbuk Samsung Health Study on 347,971 individuals (mean age: 39.6 years old; male: 57.4%; mean follow-up: 5.64 ± 3.27 years) highlighted that the lowest LDL-C group (< 70 mg/dL) was at a higher risk of all-cause mortality (HR: 1.81; 95% CI: 1.44–2.28) compared with the reference group (120–139 mg/dL) [7]. Further, it reported 2,028 deaths among the total number of participants and 11,376 (10.5%) deaths during the study among the 108,243 individuals aged 20–100 years (male: 45.0%; median follow-up: 9.4 years). The study also showed a U-shaped relationship between LDL-C levels and the risk of all-cause mortality: that is, low levels (< 70 mg/dL; HR: 1.25, 95% CI: 1.15–1.36) and high levels (> 189 mg/dL; HR: 1.15, 95% CI: 1.05–1.27) were associated with an increased risk of all-cause mortality compared with the reference group (132–154 mg/L) [16]. The China Health and Retirement Longitudinal Study (follow-up: four years) recorded a total of 305 deaths out of 4,981 male participants. Compared with the LDL-C baseline group (117–137 mg/dL), a lower LDL-C level (≤ 84 mg/dL) was associated with an increased risk of four-year all-cause mortality in middle-aged and older adult Chinese male participants [17]. According to a recent systematic review of 19 cohort studies with more than 68,094 older adults, all-cause mortality was highest in the lowest LDL-C quartile group. Study participants’ risk for all-cause mortality can be ascribed to their consumption of lipid-lowering agents and co-morbidities [18]. However, a population-based register study on 118,160 individuals aged 50 years or older without baseline statin use showed an association between high LDL-C levels and lower mortality among older adults [10]. The present study also reports that low LDL-C levels at baseline, as well as being male, older, having lower BMI, and having a history of CVD and diabetes, were linked with an increase in all-cause mortality. This finding was significant for male participants and those who did not have CKD.
This study examined the real-world association between low LDL-C levels and mortality outcomes among individuals undergoing lipid-lowering therapy and with a baseline history of CVD, hypertension, and diabetes. However, the sub-analysis shows similar notable findings for those who were not undergoing lipid-lowering therapy or had no other diseases. This result could alleviate concerns that serious illnesses may lower cholesterol shortly before death occurs. Further, the findings suggest that considerably lower LDL-C levels do not necessarily protect against all-cause mortality among community-dwelling persons who are not on lipid-lowering medication, thus supporting the lipid paradox [7]. In addition, the difference in results between male and female participants can be attributed to fewer deaths among women than men, which results in insufficient association power [17].
The mechanisms leading to increased all-cause mortality in individuals with very low LDL-C levels are not completely understood. Several explanations can be offered for these findings. Low LDL-C levels increase susceptibility to serious diseases [19]. Conversely, it has been hypothesized that frailty and illnesses lower cholesterol levels [20]. LDL-C may protect against viruses and cancers caused by viruses, and is therefore a component of innate immunity [21]. In addition, exotoxins produced by Gram-positive bacteria are absorbed by LDL-C [22] Thus, higher LDL-C levels have been associated with reduced infection-related mortality and other non-CVD mortality, which explains the inverse relationship with all-cause mortality [23]. In this study, comorbidities such as hypertriglyceridemia, low HDL cholesterolemia, and hyperuricemia were more frequently observed in individuals with the lowest LDL-C levels.