Lower LDL Levels are Not Associated with Lowest Mortality

LDL Cholesterol Levels and Mortality Risk Study: New Insights from University Researchers

A new study conducted by researchers from the University of Pittsburgh and the University of South Florida challenges the widely held belief that lower LDL cholesterol levels are always beneficial. The findings, based on extensive medical records, suggest that the relationship between LDL cholesterol and mortality risk is more complex than previously thought.

A Comprehensive Analysis of Medical Records

The researchers analyzed electronic medical records from the University of Pittsburgh Medical Center’s healthcare system, covering data from 2000 to 2022. This vast dataset included 178,000 patients aged 50 to 89, providing a robust foundation for their study.

Participants were required to meet specific criteria, including the absence of diabetes and statin therapy at baseline and during the first year of follow-up. Individuals who died within the first year of follow-up or exhibited extreme cholesterol levels were excluded to reduce the likelihood of reverse causation. The researchers categorized the sample into six LDL-C groups: 30-79, 80-99, 100-129, 130-159, 160-189, and over 190 mg/dL.

The U-Shaped Relationship Between LDL-C and Mortality

Over an average follow-up period of six years, the data revealed a U-shaped correlation between LDL cholesterol levels and 10-year all-cause mortality. The highest mortality rate (19.8%) was observed in the 30-79 mg/dL group. Mortality rates in the other groups were 14.7%, 11.7%, 10.7%, 10.1%, and 14.0%, respectively.

When compared to the reference group (80-99 mg/dL), the lowest LDL-C group (30-79 mg/dL) demonstrated a 23% increase in mortality risk. Conversely, participants within the 100-189 mg/dL range exhibited lower mortality risks than the reference group by 13%, 12%, and 9%, respectively. However, in the highest LDL-C group (over 190 mg/dL), the mortality risk was once again elevated by 19%.

Implications for Cardiovascular Disease Risk

Similar patterns emerged when analyzing the risk of atherosclerotic cardiovascular disease (ASCVD). However, in this context, the highest LDL-C group (over 190 mg/dL) exhibited the greatest risk. Interestingly, among men, even this subgroup did not display a significantly higher mortality risk than the reference category.

Triglycerides and HDL Cholesterol: More Reliable Predictors?

Beyond LDL cholesterol, the researchers identified a more consistent predictor of mortality risk: the ratio of triglycerides to HDL cholesterol (HDL-C), a measure often considered beneficial. Additionally, the total cholesterol to HDL cholesterol ratio (T-C/HDL-C) appeared to be a superior predictor of mortality compared to LDL-C levels.

“Compared with patients in the highest quintile of triglycerides/HDL-C ratio (value of ≥3.44), those in the lowest quintile (value of ≤1.06) had an estimated 24% lower risk of mortality,” the study states. “Thus, in aggregate and irrespective of age, the secondary lipid measures of T-C/HDL-C ratio and triglycerides/HDL-C ratio appeared to be more predictive of mortality than LDL-C, and a triglycerides/HDL-C ratio of about 1 or lower appears to be optimal.”

Cholesterol Ratios and Insurance Industry Insights

The study also noted that the insurance industry has already recognized the predictive value of these cholesterol ratios. Both total cholesterol and HDL-C are more commonly used in life insurance policy underwriting than LDL-C. This aligns with past instances where financial incentives have driven the insurance industry to identify health risk factors ahead of mainstream medical research.

The Need for Further Investigation

While this observational study cannot establish causality, its findings align with some previous research on LDL cholesterol and mortality risk. The authors call for further studies to explore these relationships, particularly in the context of statin use. Future research should consider both the benefits of statins in reducing cardiovascular disease and their potential side effects, such as muscle pain and an increased risk of type 2 diabetes.

“In this analysis among primary prevention-type patients without diabetes aged 50–89 years not on statin therapy at baseline or within 1 year, we found no evidence of a gradient relationship between LDL-C and long-term mortality risk. Instead, we observed that within the entire LDL-C range of 100–189 mg/dL (about two-thirds of the total patient population), mortality risk was similar and slightly lower than the referent LDL-C category of 80–99 mg/dL. These data conflict with the prevailing belief that ‘lower LDL-C is better’ yet align with results from multiple studies.”

The study’s findings suggest that LDL cholesterol alone may not be the most reliable predictor of mortality risk, emphasizing the need for a more comprehensive approach to lipid management and cardiovascular health.

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Study Links:

[1] Kip, K. E., Diamond, D., Mulukutla, S., & Marroquin, O. C. (2024). Is LDL cholesterol associated with long-term mortality among primary prevention adults? A retrospective cohort study from a large healthcare system. BMJ open, 14(3), e077949.

[2] Fulks, M., Stout, R. L., & Dolan, V. F. (2009). Association of cholesterol, LDL, HDL, cholesterol/HDL and triglyceride with all-cause mortality in life insurance applicants. J Insur Med, 41(4), 244-253.

[3] Johannesen, C. D. L., Langsted, A., Mortensen, M. B., & Nordestgaard, B. G. (2020). Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. Bmj, 371.

[4] Mansi, I. A., Chansard, M., Lingvay, I., Zhang, S., Halm, E. A., & Alvarez, C. A. (2021). Association of statin therapy initiation with diabetes progression: a retrospective matched-cohort study. JAMA internal medicine, 181(12), 1562-1574.