This study showed that higher nonHDLc/HDLc ratio, even at a low level, was associated with a higher risk of 30-day mortality among patients with sepsis in ICU. The major finding was that the probability of mortality decreased when the nonHDLc/HDLc ratio lower than the turning point (< 3.58) with a adjusted OR of 0.75 (95% CI: 0.61–0.94, P = 0.011) for every 1 increment of nonHDLc/HDLc ratio. To our knowledge, this is the first study to report the relation between the nonHDLc/HDLc ratio and 30-day mortality in adult ICU patients with sepsis.
Most studies investigating the relation between levels of LDL-C and the risk of all cause mortality have found no association[13–15] or an inverse association[16–18]. You et al.[19] included 356 patients with intracranial hemorrhage (mean follow-up = 0.22 years) and found that the LDL-C/HDL-C ratio was negatively correlated with all-cause mortality, they suggested that the LDL-C/HDL-C ratio should be controlled above 2.96. Liu et al.[20] recruited 3250 stroke patients (mean follow-up = 1.00 years) and found a negative relationship between the LDL-C/HDL-C ratio and all-cause mortality. The findings of the above studies suggest that the relationship between the LDL-C/HDL-C ratio and all-cause mortality may be negative, and the proposed optimal range of the LDL-C/HDL-C ratio has been inconsistent. These conflicting results can be attributed to differences in the study populations, follow-up durations, and end-point events. Consequently, the relationship between the nonHDLc/HDLc ratio and all-cause mortality are still unclear, which prompted us to conduct the current study.
We used non-HDL cholesterol rather than LDL cholesterol because in our database had measured TC and HDL cholesterol, from which non-HDL cholesterol can be calculated by subtraction. LDL cholesterol was directly measured in only 72% of patients. Further, the most commonly used estimation method, i.e. the Friedewald equation, can be inaccurate[21]. That non-HDL and LDL cholesterol were correlated in studies with data on both variables (r = 0.93)[4]. Non-HDL cholesterol predicts CHD risk at least as well as LDL cholesterol[22] because it includes cholesterol in LDL, lipoprotein(a), intermediate-density lipoprotein, very-low-density lipoprotein and lipoprotein remnants, and is thus a simple measure of cholesterol content within all atherogenic lipoproteins.
Also, a recent study in a Chinese Hypertension Registry study of 6941 hypertensive patients aged 65 years or older who were not treated with lipid-lowering drugs, during a median follow-up of 1.72 years, 157 all-cause deaths occurred, a U-shaped relationship between the LDL-C/HDL-C ratio and all-cause mortality was found. The optimal range of the LDL-C/HDL-C ratio was 1.67–2.10[8], similar to our results that mortality in relation to the nonHDLc/HDLc ratio was U-shaped.
Possible explanations for our findings. The association between low levels of nonHDLc and an increased risk of all cause mortality could be explained by reverse causation. Debilitation and illness have been hypothesised to cause a decrease in levels of cholesterol[23, 24]. Nonetheless, cholesterol-related risk is more complex, and involves the interplay of several factors such as cholesterol particle concentration, reverse cholesterol transport and triglyceride-rich lipoproteins, to mention a few[25]. The U shaped association between the nonHDLc/HDLc ratio and mortality might be similar to the obesity paradox, which is largely explained by methodological issues, including reverse causation[26].
The current study is based on a ICU data, could be important for understanding what is a “normal and healthy” the nonHDLc/HDLc ratio in patients with sepsis (that is, when the focus is not limited to myocardial infarction and atherosclerotic cardiovascular disease). Explored the threshold the nonHDLc/HDLc ratio level where risk of death significantly increases is a high priority in patients with sepsis.
Study limitations
One limitation of this study is inherent to the observational nature of the study design which lends itself subject to limitations that should be considered including confounding by indication. Our findings are hypothesis-generating and do not imply causality. In our analysis, we adjusted for likely confounders, including age, sex, ethnicity, serum creatinine, systolic blood pressure, pneumonia and COPD. Despite this adjustment, it is still possible that some amount of unmeasured confounding remains. Additional limitations of our study include missing data for some variables. Nonetheless, we used contemporary methods to deal with missing data to minimize bias.
Another limitation relates to the fact that the diagnoses were based on the ICD-9 coding which the responsible physician found relevant, and we did not have information concerning causes of death. Since we are examining mortality over a short period after the date of visit to the ICU, we did not find it beneficial to distinguish between cardiovascular and non-cardiovascular death.
Furthermore, we lacked information about interventions during the initial stabilization, which may have influencedthe nonHDLc/HDLc ratio levels and survival. It is noteworthy that the potential resulting from interventions would bias toward to the null and thus result in an underestimation of the association betweenthe nonHDLc/HDLc ratio level and mortality.
Finally, we also acknowledge that as our participants were patients referred for any reason to the emergency department, which limits the generalizability of the findings to other population.