A large retrospective cohort study found that among primary prevention adults aged 50 to 89 years without diabetes who weren't receiving statin therapy, the lowest risk for long-term mortality was observed in those with low-density lipoprotein cholesterol levels between 100 and 189 mg/dL. This range was considerably higher than current recommendations for optimal low-density lipoprotein cholesterol levels.

In the study, published in BMJ Open, investigators analyzed the data from 177,860 adults over a mean follow-up period of 6.1 years. The findings challenged the prevailing belief that low-density lipoprotein (LDL) cholesterol is better for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and mortality.

The investigators utilized electronic medical record data from the University of Pittsburgh Medical Center health care system for adults aged 50 to 89 years from January 4, 2000, through December 31, 2022.

Inclusion criteria were:

• No history of diabetes, coronary artery disease, carotid artery disease, peripheral vascular disease, cardiac arrest, hemorrhagic or ischemic stroke, or transient ischemic attack
• Not on statin therapy at baseline or within 1 year of follow-up
• Survival for at least 1 year after baseline cholesterol measurement
• Baseline total cholesterol > 120 mg/dL and LDL cholesterol ≥ 30 mg/dL.

The primary outcome was all-cause mortality, with follow-up starting 365 days after baseline cholesterol measurement. Secondary analyses included a composite outcome of ASCVD events.

Among the key findings were:

• A U-shaped relationship was observed between LDL cholesterol categories and mortality, with crude 10-year mortality rates of 19.8%, 14.7%, 11.7%, 10.7%, 10.1%, and 14.0% for LDL cholesterol categories of 30 to 79, 80 to 99, 100 to 129, 130 to 159, 160 to 189, and ≥ 190 mg/dL, respectively.
• Adjusted mortality hazard ratios (HR) compared with the referent group of LDL cholesterol 80 to 99 mg/dL were: 30 to 79 mg/dL (HR = 1.23, 95% confidence interval [CI] = 1.17–1.30), 100 to 129 mg/dL (HR = 0.87, 95% CI = 0.83–0.91), 130 to 159 mg/dL (HR = 0.88, 95% CI = 0.84–0.93), 160 to 189 mg/dL (HR = 0.91, 95% CI = 0.84–0.98), and ≥ 190 mg/dL (HR = 1.19, 95% CI = 1.06–1.34).
• Total cholesterol/high-density lipoprotein (HDL) cholesterol and triglycerides/HDL cholesterol ratios were independently associated with long-term mortality, while LDL cholesterol appeared to have limited predictive value.
• The lowest risk for ASCVD events was also observed in the LDL cholesterol range of 100 to 189 mg/dL.

The mean age of participants was 61.1 (standard deviation [SD] = 8.8) years, and the mean LDL cholesterol was 119 (SD = 31) mg/dL. The study population was predominantly White (94.4%) and female (61.5%). The median systolic blood pressure was 128 mmHg (interquartile range [IQR] = 118–139), and the median diastolic blood pressure was 80 mmHg (IQR = 71–84).

LDL cholesterol distribution among participants was: 30 to 79 mg/dL (9.1%), 80 to 99 mg/dL (18.3%), 100 to 129 mg/dL (39.1%), 130 to 159 mg/dL (24.4%), 160 to 189 mg/dL (7.1%), and ≥ 190 mg/dL (2.0%).

Comorbidities included history of obesity (38.8%), hypertension (34.1%), atrial fibrillation (2.8%), cancer (8.0%), chronic obstructive pulmonary disease (4.5%), and depression (12.0%).

Medication use at baseline included ACE inhibitors (11.6%), beta-blockers (12.9%), calcium channel blockers (9.5%), diuretics (12.7%), antidepressants (19.9%), and aspirin (18.0%).

The median ASCVD 10-year risk score was 5.9% (IQR = 2.8–12.3), with 58.6% classified as low risk, 28.8% as intermediate risk, and 12.6% as high risk.

Subgroup analyses by age (50 to 69 and 70 to 89 years), sex, and baseline ASCVD risk classification showed consistent results, with the lowest mortality risk observed in the LDL cholesterol range of 100 to 189 mg/dL.

For the total cholesterol/HDL cholesterol ratio, patients with a ratio > 6.0 had a significantly higher risk of mortality compared with those with a ratio ≤ 3.0 (adjusted HR = 1.28, 95% CI = 1.18–1.38). The triglycerides/HDL cholesterol ratio showed the most consistent evidence of a gradient relationship with mortality, with lower values progressively conferring lower risk. Compared with patients in the highest quintile of triglycerides/HDL cholesterol ratio (value of ≥ 3.44), those in the lowest quintile (value of ≤ 1.06) had an estimated 24% lower risk of mortality (adjusted HR = 0.76, 95% CI = 0.72–0.81).

ASCVD outcomes showed a similar U-shaped relationship with LDL cholesterol categories. The 10-year cumulative incidence of ASCVD was 6.5%, 5.3%, 4.7%, 4.8%, 5.1%, and 7.6% for LDL cholesterol categories of 30 to 79, 80 to 99, 100 to 129, 130 to 159, 160 to 189, and ≥ 190 mg/dL, respectively.

Statin initiation rates more than 1 year after baseline measurement increased with higher LDL cholesterol levels, ranging from 3.0% in the 30 to 79 mg/dL group to 18.0% in the ≥ 190 mg/dL group.

Limitations of the study included the inability to assess cause-specific mortality, potential bias because of reverse causation (despite efforts to mitigate this), and possible residual confounding despite adjustment for numerous covariates.

The authors declared having no competing interests.