Original Research

How Low Is Too Low? A Retrospective Analysis of Very Low LDL-C Levels in Veterans

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Background: Low-density lipoprotein cholesterol (LDL-C) can build up on the walls of blood vessels, leading to coronary heart disease. Medications used to lower LDL-C levels have demonstrated decreased risks of atherosclerotic cardiovascular disease, but currently, there is no consensus on how to define very low LDL-C levels. It is necessary for the body to have LDL-C to maintain proper brain function; however, the safety and effects of prolonged very low LDL-C levels are unknown. The current study sought to gather information to determine the risks of very low LDL-C levels in a veteran population.

Methods: A retrospective chart review was conducted at a US Department of Veterans Affairs medical center. Patients with hyperlipidemia/dyslipidemia treated with HMG-CoA reductase inhibitors or proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy and LDL-C levels < 40 mg/dL between January 1, 2010, and September 1, 2020, were included. The primary outcome was the rate of intracranial hemorrhage that could be caused by an LDL-C level < 40 mg/dL. The secondary outcomes included actions taken by clinicians, adverse drug reactions (ADRs), duration of therapy, and medication adherence.

Results: This study included 3027 patients. Of the included patients, 8 had an intracranial hemorrhage within 1 year from a documented LDL-C level < 40 mg/dL (0.26%). Thirty-two patients with an LDL-C level < 40 mg/dL did not have a documented ADR with the studied medications. Of the 32 charts, 26 had a clinician address the LDL-C level < 40 mg/dL with either documentation and/or modification of the medication prescribed. The most common ADRs among the studied medications were muscle and joint pain, rash, and cramps. Adherence to the medications was consistently similar for all studied medications.

Conclusions: Of the patient population included in this study, 0.26% of patients had an intracranial hemorrhage within 1 year of having an LDL-C level < 40 mg/dL. The rate of ADRs related to the medications analyzed in this study shows no statistical significance ( P > .05). When compared with low- and moderate-intensity statin medications, high-intensity statin medications were statistically significant in resulting in an LDL-C level < 40 mg/dL ( P < .001). LDL-C levels < 40 mg/mL were not routinely documented as being addressed in the chart by the clinician.



According to the Centers for Disease Control and Prevention (CDC), approximately 795,000 strokes occur in the United States yearly and are the fifth leading cause of death.1 The CDC also states that about 43 million Americans who could benefit from cholesterol medication are currently taking them.2 As of 2019, West Virginia, Ohio, and Kentucky are 3 states with the highest rates of heart disease mortality.3

Low-density lipoprotein cholesterol (LDL-C) accumulates on the walls of blood vessels, which can lead to coronary heart disease. However, some LDL-C is necessary to maintain proper brain function. Guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) recommend LDL-C goal levels < 70 mg/dL.4 Yet, there is no consensus on how low LDL-C levels should be. According to clinical practice guidelines for dyslipidemia, developed by the US Department of Veterans Affairs (VA) and US Department of Defense, statin medications are first-line agents for lowering LDL-C. The intensity of the statin medication is based on primary or secondary prevention, atherosclerotic cardiovascular disease (ASCVD) risk, and current LDL-C levels prior to treatment.5

Statin medications are used for primary and secondary prevention of ASCVD. In addition, statin medications decrease total cholesterol, LDL-C, and triglycerides while causing a mild increase in high-density lipoprotein cholesterol. Although statin medications are first-line therapy for LDL-C lowering, other medications can be used to assist in decreasing LDL-C. Ezetimibe, fenofibrates, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can also be used.5 Statin medications do pose a risk of severe adverse drug reactions (ADRs), such as rhabdomyolysis and myopathy.6

One prospective cohort study looked at 27,937 women and analyzed total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, and strokes. The study noted a mean 19.3-year follow-up and within that follow-up, 137 hemorrhagic strokes occurred. Based on the study’s results, LDL-C levels < 70 mg/dL had 2.17 times the risk of experiencing a hemorrhagic stroke.7 A meta-analysis of prospective studies analyzed 476,173 patients and 7487 hemorrhagic stroke cases. This review concluded that a 10 mg/dL increase in LDL-C was associated with a 3% lower risk of hemorrhagic stroke.8

An observational study conducted in Asia of Chinese adults found that 22% of all strokes were hemorrhagic. The incidence of the hemorrhagic strokes was higher for patients who had an LDL-C < 1.8 mmol/L than those who had an LDL-C between 1.8 and 2.6 mmol/L. This study also showed that if hypertension was inadequately treated, the risk of hemorrhagic stroke increased. This study concluded that the benefit of reducing ASCVD outweighs the small risk of hemorrhagic strokes.9

Another prospective cohort study included 96,043 stroke-free participants and analyzed LDL-C concentrations and incidence of intracranial hemorrhage. The average LDL-C concentrations were calculated from data collected in 4 separate reporting years, and incidence of intracranial hemorrhage was confirmed through review of medication records. Over a 9-year follow-up period, the study concluded that participants with an LDL-C level of < 70 mg/dL had a significantly higher risk of developing intracranial hemorrhage than participants with LDL-C levels 70 to 99 mg/dL.10

The safety and effects of prolonged very low LDL-C levels are currently unknown. The current study sought to gather information to determine the risks of very low LDL-C levels in a veteran population.


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