Low-Density Lipoprotein Cholesterol: How Low Should You Go? And What About Safety?
ABSTRACT: Targets for low-density lipoprotein cholesterol (LDL-C) levels with treatment recently have been abandoned by some experts, leaving clinicians in a quandary about how to judge the efficacy of dyslipidemia therapy. Other experts believe in the value of targets because of the residual risk that remains, even after a target of LDL-C below 70 mg/dL has been reached. In some studies, residual risk has been shown to be more than 50% even after LDL-C levels have been reduced significantly. A newer pharmacotherapeutic option, PCSK9 inhibitors added to statins, has demonstrated significant reductions in LDL to as low as 25 mg/dL and has been shown to be safe for at least 1 year. The question now becomes how low do you need to go, and whether a very low LDL-C level will be safe. Reductions of LDL-C to 50 mg/dL have been associated with plaque regression and appear to be safe. This article reviews these issues and offer suggestions for reaching a safe lower LDL-C limit.
KEYWORDS: Low-density lipoprotein cholesterol (LDL-C), hypercholesterolemia, dyslipidemia, PCSK9 inhibitors, statins, cardiovascular disease
A number of experts recently have abandoned the notion of target levels for low-density lipoprotein cholesterol (LDL-C) with treatment, leaving clinicians in a quandary about how to judge the efficacy of cholesterol-lowering therapy. Other experts continue to believe in the value of LDL-C target levels because of the residual risk that remains even when patients achieve a traditional target level of less than 70 mg/dL. In some studies, the residual risk can be greater than 50% even after LDL-C levels have been significantly reduced.
A newer treatment option, proprotein convertase subtilisin-like kexin type 9 (PCSK9) inhibitors added to statins, demonstrates significant reductions in LDL-C to as low as 25 mg/dL, and the regimen appears to be safe for at least 1 year. The question now becomes how low do you need to go, and will a very low LDL-C be safe in the long term. Reductions of LDL-C to 50 mg/dL have been associated with plaque regression and appear to be safe.
What value is a lower LDL-C?
It is clear that high serum cholesterol levels, and specifically high levels of LDL-C, is associated with an increased risk of cardiovascular disease (CVD), and it is clear that reducing LDL-C reduces the incidence of cardiovascular events. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guideline suggests a 50% reduction in LDL-C in high-risk patients but sets no specific goal.1 This approach is appropriate for patients who have a lower baseline LDL-C level but may not be appropriate if the baseline level is higher, such as 160 mg/dL.
The National Lipid Association (NLA) recommends an LDL-C goal of less than 70 mg/dL for high-risk patients.2 The Cholesterol Treatment Trialists’ meta-analysis demonstrated that every 38.7 mg/dL drop in LDL-C corresponded with a 22% relative risk reduction across the spectrum of LDL levels.3 Another meta-analysis demonstrated a linear reduction in risk down to an LDL-C level of 50 mg/dL.4 In this study, individuals with LDL-C levels less than 50 mg/dL had a significantly lower risk of major cardiovascular events compared with individuals who had higher LDL-C levels, including those with levels of 50 to 74 mg/dL and 75 to 99 mg/dL.
What value is LDL-C Itself?
We understand that exposure to high levels of LDL-C over time leads to CVD, but our bodies do need LDL-C. So the question is, how much, and how low can we lower serum LDL without creating safety issues?
The role of low-density lipoproteins is to transport fats (triglycerides and cholesterol) through water inside and outside the cells. Cholesterol is not water-soluble, so it requires a lipoprotein for transport. Cholesterol is required for cell membrane integrity and is a precursor for synthesis of vitamin D, steroid hormones such as cortisol and aldosterone, and the sex hormones progesterone, estrogen, and testosterone.5 LDL-C levels of 50 mg/dL do not appear to lead to problems with the transport mechanism, but more data are needed to prove that levels below 25 mg/dL will not be problematic.
The publication of ACC/AHA guideline on treatment of blood cholesterol1 in 2014 created confusion and doubt about the use of LDL-C targets to guide treatment. The ACC/AHA guideline recommended a 50% reduction in baseline LDL-C for high-risk patients using high-intensity statins and no specific target for treatment. The NLA2 and others maintain that targets are important, and they should guide treatment decisions. The NLA’s recommended target is less than 70 mg/dL for high-risk patients. The NLA’s view is that targets ensure aggressiveness of therapy to lower the absolute risk for an event.
Treatment targets also facilitate effective communication between patients and clinicians and provide a means to communicate progress towards objectives. The recent publication of IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)6 added additional strength to the idea of lipid targets by demonstrating that the combination of ezetimibe and the statin simvastatin achieved an average on-treatment LDL-C of 54 mg/dL versus 70 mg/dL for simvastatin monotherapy, and this further LDL-C lowering was associated with a 6% relative reduction in arteriosclerotic cardiovascular disease (ASCVD). The Cholesterol Treatment Trialists’ Collaboration3 found that for every 38 mg/dL reduction in LDL-C, there was an associated 22% relative reduction in ASCVD events. The weight of evidence from multiple studies supports a strong dose-response relationship between LDL-C and ASCVD. The longer the exposure to high LDL-C, the greater the chance of the development of ASCVD. This relationship leads to the concept that elevations in LDL-C should be addressed earlier in the lifespan in order to reduce the incidence of ASCVD.
Plaque regression Vs stabilization
There seems to be agreement that a high LDL-C level leads to CVD, but there is disagreement about how low LDL-C levels can or should go. An expert opinion goal of less than 70 mg/dL is popular, but significant residual risk remains for patients on statins who achieve an LDL-C goal of below 70 mg/dL. Recent publications suggest that plaque stabilization occurs when LDL-C is below 70 mg/dL, but plaque regression will not occur until LDL is below 50 mg/dL.7
The REVERSAL trial (Reversal of Atherosclerosis With Aggressive Lipid Lowering)8 comparing high-dose statin therapy with a less-potent statin regimen for 18 months demonstrated progression of disease in the group receiving the less-potent statin therapy who had LDL-C levels averaging 110 mg/dL. The high-dose statin group experienced no significant progression of atheroma volume with an average LDL-C level of 79 mg/dL. LDL reduction exceeding approximately 50% was associated with a decrease in atheroma volume.
In the ASTEROID trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden),9 patients received the same high-dose therapy for 24 months. Pretreatment and posttreatment LDL-C and intravascular ultrasonography findings were compared. With treatment, LDL-C dropped to an average of 60.8 mg/dL and atheroma volume shrank by 6.8%. The reductions in plaque volume are accompanied by favorable alterations in plaque biology, a theory that is supported by evidence showing that robust plasma LDL-C lowering (≤ 40-60 mg/dL) is associated with further reductions in the occurrence of cardiovascular events.7
high triglyceride levels and LDL levels
At times, a low LDL-C level is a result of high triglyceride (TG) levels. High serum TG levels mathematically decrease LDL-C levels when the LDL-C is measured through indirect methodology using the Friedewald equation,10 where TC is total cholesterol and HDL-C is high-density lipoprotein cholesterol:
LDL-C = TC – HDL-C − (TG/5)
This is the most common way LDL-C is measured on laboratory reports. When LDL-C is measured by direct analysis via ultracentrifuge, the levels are more accurate. The majority of the time, however, lipid panels obtained in clinical practice use the Friedewald equation to calculate LDL-C levels.
An example would be a TC level of 200 mg/dL, an HDL-C level of 40 mg/dL, and a TG level of 250 mg/dL; using the Friedewald equation, the LDL-C in this case is 110 mg/dL, calculated as 200 – 40 – 50 (the quotient of 250 divided by 5). If the TG level were 100 mg/dL, the LDL would then be 140 mg/dL (200 – 40 – 20 = 140). A higher TG level led to a lower calculated LDL-C level.
So it is important to realize that a low LDL-C level combined with a high TG level creates a false impression. Once the TG is lowered, the LDL-C value will increase.
LDL-C values Below 50 mg/dl
The recent introduction of PCSK9 inhibitors combined with statins to treat elevated LDL-C levels has demonstrated even more significant reductions in LDL to as low as 25 mg/dL.11,12 In the OSLER (Open-Label Study of Long-Term Evaluation Against LDL-C)12 randomized trial clinical trial,12 patients treated with evolocumab had at least one LDL-C value less than 25 mg/dL. Dosing was not modified or interrupted because of the low LDL-C level, and the patients were followed for 1 year. Serious adverse events in the evolocumab-treated group were similar as in the standard-of-care group (2.3% to 2.9%) for LDL-C levels of less than 25 mg/dL, less than 40 mg/dL, and greater than 40 mg/dL. Patients will need to be followed for more than a year to provide clearer evidence of safety, but the initial data seem to point to safety for LDL levels less than 25 mg/dL.11,12
Summary and recommendations
Several studies indicate that a decrease of LDL-C to levels of 40 to 60 mg/dL reduces ASCVD and is safe. Some studies indicate that reduction of LDL to below 25 mg/dL is safe and reduces ASCVD, but the published studies only have followed patients for 1 year. More time will be needed to determine whether LDL-C reductions to less than 25 mg/dL can be recommended.
Medication regimens that are associated with reduced ASCVD occurrence include statins and statins combined with ezetimibe. PCSK9 inhibitors combined with statins in clinical trials have been shown to produce a 60% to 70% reduction in LDL-C beyond that attained with statins alone.
Longer outcomes studies are needed to compare ASCVD reduction with statins alone or statins plus ezetimibe. Given the current state of our knowledge, it seems safe to reduce LDL-C levels to 40 to 60 mg/dL, but more time is needed to be more assured about levels below 25 mg/dL. Even when LDL is reduced to below 70 mg/dL, significant residual risk remains. Some of that risk can be reduced with better control of blood pressure and blood glucose levels and other risk factors such as obesity and tobacco use. But high-risk patients who are not able to decrease their LDL-C level because of statin intolerance or who are hyporesponders to statins need additional medication. Ezetimibe and PCSK9 inhibitors are the next in line treatments of choice.
Edward Shahady, MD, ABCL, is a clinical professor of family medicine at the University of Florida and the University of Miami and is president and medical director of the Diabetes Master Clinician Program in Fernandina Beach, Florida.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.
- Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol. 2015;9(2):129-169.
- Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
- Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64(5): 485-494.
- Hanukoglu I. Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. J Steroid Biochem Mol Biol. 1992;43(8):779-804.
- Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015; 132(13):1224-1233.
- Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E; PROVE IT-TIMI 22 Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46(8):1411-1416.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9): 1071-1080.
- Nissen SE, Nicholls SJ, Sipahi I, et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13): 1556-1565.
- Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18(6):499-502.
- Robinson JG, Nedergaard BS, Rogers WJ, et al; LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18): 1870-1883.
- Koren MJ, Giugliano RP, Raal FJ, et al; OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014;129(2):234-243.