Clinical Conundrum: The Estimated LDL-C Below 40 mg/dL

Recent clinical trial data has strengthened the argument that lowering low-density lipoprotein cholesterol (LDL-C) to levels well below those previously targeted provides incremental benefit in terms of lowering the risk of atherosclerotic cardiovascular disease (ASCVD).¹ The increased use of high-intensity statins, irrespective of baseline LDL-C, has resulted in clinicians more frequently encountering LDL-C levels below 40 mg/dL. The 2013 American College of Cardiology/ American Heart Association (ACC/AHA) blood cholesterol guidelines suggest considering a statin dose reduction when LDL-C is persistently <40 mg/dL.² This recommendation may be misconstrued as meaning LDL-C levels <40 mg/dL are harmful and may carry the unintended consequence of patients at high risk for ASCVD receiving a statin that is less than the recommended intensity. Furthermore, LDL-C levels below 40 mg/dL, as estimated by the Friedewald equation [LDL-C = (total cholesterol) – (HDL-C) – (TG/5)], often are inaccurate in the setting of elevated triglyceride (TG) levels.³ What follows is a discussion focused on how clinicians caring for patients at risk for ASCVD may interpret very low levels of LDL-C, including practical suggestions for how to approach this clinical conundrum.

Historically speaking, there has been limited experience with extremely low levels of LDL-C. Gestational and neonatal LDL-C levels have been reported to be in the range of 30–70 mg/dL and individuals with familial hypobetalipoproteinemia have LDL-C levels in the range of 0–20 mg/dL for homozygotes and 30–50 mg/dL for heterozygotes.^4,5 In the past decade, contemporary clinical trials have reported increased numbers of patients with LDL-C levels <40 mg/dL (Table 1).^1,6–10

The basis for the ACC/AHA recommendation stems from the treatment approach employed in certain clinical trials in which an LDL-C <40 mg/dL was an arbitrary threshold set for investigators to consider a down titration of statin therapy.^11,12 In fact, the ACC/AHA detailed supplemental full panel report states that there is no evidence of harm when LDL-C remains <40 mg/dL on statin therapy, a point which is echoed in the 2014 National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia.^2,13

In the Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) trial, which compared atorvastatin 80 mg a day to simvastatin 20–40 mg a day in patients with a history of myocardial infarction (MI) (baseline LDL-C 121 mg/dL), investigators were given the option to decrease statin doses if LDL-C fell below 39 mg/dL.¹¹ Similarly, in the HDL Atherosclerosis Treatment Study (HATS) trial, which compared various doses of simvastatin in combination with niacin in patients with angiographic evidence of coronary artery disease (baseline LDL-C 125 mg/dL), investigators were given the option to reduce the statin dose if LDL-C was <40 mg/dL.¹² Conversely, in the Collaborative Atorvastatin Diabetes Study (CARDS) trial, which compared atorvastatin 10 mg a day to placebo in patients with diabetes (baseline LDL-C 117 mg/dL) the study drug was continued regardless of LDL-C level and the data and safety monitoring board did not identify any safety concerns in patients with LDL-C <39 mg/dL.¹⁴ In patients at very high risk for ASCVD events, the NLA guidance recommends against statin dose reduction when LDL-C measures <40 mg/dL, presuming there are no tolerability- or safety-related concerns.¹³ Support for this recommendation can be found in data from both the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) and the Long-Term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia not Adequately Controlled with Their Lipid Modifying  Therapy  (ODYSSEY LONG TERM) PCSK9 inhibitor trials, wherein safety analyses of patients obtaining LDL-C <40 mg/dL, and even those <25 mg/dL, showed adverse event rates similar to those with LDL-C >40 mg/dL.^6,7

Most laboratories report Friedewald estimated LDL-C unless TG are >400 mg/dL, in which case a direct LDL-C is reported. However, research by Martin and colleagues has demonstrated that even at mildly elevated TG levels (i.e. >150 mg/dL), the Friedewald equation becomes increasingly inaccurate at lower levels of LDL-C.^3,15 The reason for the discrepancy between estimated and directly measured LDL-C stems from the fact that the equation assumes a fixed ratio (5:1) of TG to VLDL-C. Employing  a fixed factor of 5 to estimate VLDL-C from TG creates a problem in that TG:VLDL-C ratio is not constant across a range of TG and total cholesterol (TC) values. To get around this problem, one should assess non-high-density lipoprotein cholesterol (non- HDL-C) levels, which is the primary goal of therapy in the NLA Recommendations, or consider using an adjustable factor for the TG:VLDL-C ratio based off TG.^13,15

A recent scenario encountered in our practice involved a 68-year-old patient with established ASCVD (MI w/stent in 2014) and diabetes mellitus taking atorvastatin 40 mg once daily. A fasting lipid panel revealed: TC 136, TG 385, HDL-C 42, LDL-C 17, and non-HDL-C 94 mg/dL. Since triglycerides were <400 mg/dL, the reported LDL-C represented a Friedewald estimation. Her primary care physician expressed concern about the patient’s LDL-C being too low and suggested a reduction in atorvastatin dose. In this scenario, one could start by pointing out that non-HDL-C is near 100 mg/dL, which would provide rationale for not decreasing the statin dose to maintain the recommended intensity of statin and ensure optimal ASCVD risk reduction. Next, using a method proposed by Martin, et al.,¹⁵ the TG:VLDL-C ratio would be 9.5, which would yield an estimated LDL-C of 53 mg/dL. Finally, one could request that the laboratory parse out a direct LDL-C from the blood sample. In fact, this was performed in this case and the directly measured LDL-C was 52 mg/dL. Each of these strategies should lead to the same conclusion for this patient: It is reasonable to continue atorvastatin at the current dose.

A growing body of evidence suggests that LDL-C levels can be safely driven to very low levels in individuals at high risk for ASCVD. Clinical outcomes data from PCSK9 inhibitor trials are anticipated in the near future and may address some of the safety concerns that have been raised with treating to very low LDL-C levels (eg. hemorrhagic stroke and cognitive effects). When an LDL-C <40 mg/dL is encountered, a statin dose reduction may not be necessary, particularly in patients at high risk for ASCVD. Exceptions might include the presence of advanced age, statin drug interactions, or patient- reported side effects. Further complicating matters is the fact that when TG are elevated and LDL-C is driven to very low levels, the accuracy of the Friedewald equation is severely compromised. When concerns arise over a seemingly “too low” LDL-C and direct measurement is impractical, it is important to remember that non-HDL-C serves as an inexpensive means by which to estimate circulating levels of atherogenic particles. Taking these steps may help to minimize inappropriate statin dose reductions in patients with LDL-C below 40 mg/dL.

Disclosure statement: Dr. Lamprecht has no disclosures to report. Dr. Stadler has no disclosures to report.

References are listed on page 45 of the PDF.