Is LDL cholesterol associated with long-term mortality among primary prevention adults? A retrospective cohort study from a large healthcare system

Abstract

Objectives: Among primary prevention-type adults not on lipid-lowering therapy, conflicting results exist on the relationship between low-density lipoprotein cholesterol (LDL-C) and long-term mortality. We evaluated this relationship in a real-world evidence population of adults.

Design: Retrospective cohort study.

Setting: Electronic medical record data for adults, from 4 January 2000 through 31 December 2022, were extracted from the University of Pittsburgh Medical Center healthcare system.

Participants: Adults without diabetes aged 50-89 years not on statin therapy at baseline or within 1 year and classified as primary prevention-type patients. To mitigate potential reverse causation, patients who died within 1 year or had baseline total cholesterol (T-C) ≤120 mg/dL or LDL-C <30 mg/dL were excluded.

Main exposure measure: Baseline LDL-C categories of 30-79, 80-99, 100-129, 130-159, 160-189 or ≥190 mg/dL.

Main outcome measure: All-cause mortality with follow-up starting 365 days after baseline cholesterol measurement.

Results: 177 860 patients with a mean (SD) age of 61.1 (8.8) years and mean (SD) LDL-C of 119 (31) mg/dL were evaluated over a mean of 6.1 years of follow-up. A U-shaped relationship was observed between the six LDL-C categories and mortality with crude 10-year mortality rates of 19.8%, 14.7%, 11.7%, 10.7%, 10.1% and 14.0%, respectively. Adjusted mortality HRs as compared with the referent group of LDL-C 80-99 mg/dL were: 30-79 mg/dL (HR 1.23, 95% CI 1.17 to 1.30), 100-129 mg/dL (0.87, 0.83-0.91), 130-159 mg/dL (0.88, 0.84-0.93), 160-189 mg/dL (0.91, 0.84-0.98) and ≥190 mg/dL (1.19, 1.06-1.34), respectively. Unlike LDL-C, both T-C/HDL cholesterol (high-density lipoprotein cholesterol) and triglycerides/HDL cholesterol ratios were independently associated with long-term mortality.

Conclusions: Among primary prevention-type patients aged 50-89 years without diabetes and not on statin therapy, the lowest risk for long-term mortality appears to exist in the wide LDL-C range of 100-189 mg/dL, which is much higher than current recommendations. For counselling these patients, minimal consideration should be given to LDL-C concentration.

Keywords: adult cardiology; epidemiology; primary prevention.

Figure 1

Plot of cumulative mortality rates in 6-month intervals over 12 years of follow-up by baseline low-density lipoprotein cholesterol (LDL-C) category. Dashed lines depict the three lowest LDL-C categories (30–79, 80–99 and 100–129 mg/dL) and solid lines depict the highest LDL-C categories (130–159, 160–189 and ≥190 mg/dL).

Figure 2

Plot of mortality HRs (filled circles) and 95% CIs (vertical lines) across categories of LDL cholesterol (top), total cholesterol to HDL cholesterol ratio (middle) and triglycerides to HDL cholesterol ratio (bottom). The left side of the graph is for patients aged 50–69 years; the right side is for patients aged 70–89 years. The dashed line reflects the referent group null value (1.0) for the HR. Q: quintile. Each model is adjusted for age, race, sex, BMI, current smoker, former smoker and history of the following in the past year: hypertension, atrial fibrillation, arrhythmia, congestive heart failure, cancer, chronic obstructive pulmonary disease, chronic kidney disease, baseline systolic and diastolic blood pressure, glucose and the following medications in the past year: ACE inhibitors, beta-blockers, calcium blockers, any SBP lowering medication, diuretics, aspirin, DOACs, antidepressants, opioids and statin initiation >1 year after baseline cholesterol measurement. BMI, Body Mass Index; DOAC, direct oral anticoagulant; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic blood pressure.