Is LDL-C Measurement Better Than Estimating Absolute Risk for Treating Increased Cholesterol? | Expert Analysis

Editor's Note: Dr. Martin is supported by the Pollin Fellowship in Preventive Cardiology, the Marie-Josée and Henry R. Kravis endowed fellowship, and an NIH training grant (T32HL07024).

According to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) prevention guidelines, a patient's absolute 10-year risk estimate is the key number to know.1-5 A low-density lipoprotein cholesterol (LDL-C) measurement alone cannot qualify a patient for statin therapy unless it is 190 mg/dL or more. The cholesterol treatment guidelines emphasize absolute risk in the allocation of statin treatment, recommending a moderate- to high-intensity statin in groups with high absolute risk. The guidelines also say that consideration of LDL-C is important on the front and back ends of decision-making when treating increased cholesterol in a given patient.

Elegant analyses by the Cholesterol Treatment Trialists have tied the relative risk reduction (RRR) to LDL-C with an approximately 20% RRR for every 39 mg/dL (1 mmol/L) reduction in LDL-C.6 Therefore, the magnitude of the RRR in a given patient is dependent on his or her baseline LDL-C is, because for any given percentage lowering, a higher baseline LDL-C will translate into more milligrams per deciliter that LDL-C is lowered. For example, consider two patients who have 55% LDL-C reductions with a high-intensity statin. If one patient has a low baseline LDL-C (70 mg/dL), that patient will benefit from a smaller RRR compared to a patient with a high baseline LDL-C (180 mg/dL) (RRR ~20% vs. ~50%, respectively). Therefore, a patient with a higher baseline LDL-C measurement would be expected to get more lipid-lowering benefits from statin therapy, and presumably more RRR, making them good candidates for using LDL-C measurement to help guide cholesterol therapy.

Measurement of LDL-C is an important topic that we have previously discussed on this site. Various methods exist for estimation and direct measurement.7-9 Among these, Friedewald estimated LDL-C7 has been used most commonly in clinical trials and clinically. Our group has proposed a novel algorithm8 for LDL-C estimation that appears to improve upon Friedewald estimation, particularly in classification of LDL-C levels <70 mg/dL, but awaits external validation. Given inherent challenges in estimating LDL-C, some clinicians may consider direct measurement of LDL-C based on the clinical context (e.g., high-risk patient, high triglycerides, low LDL-C) as well as the cost and performance characteristics of the available LDL-C test.

As noted in the 2013 ACC/AHA guidelines,2 LDL-C was directly measured in some clinical trials (HPS and IDEAL). The guidelines also note that Friedewald estimated LDL-C is "useful only when triglyceride levels are <400 mg/dL and the Type III abnormality is not present" and that biological and seasonal variations occur. Since LDL-C levels of 70 and 190 mg/dL are key cut-points in the guidelines, inaccuracies in measurement and classification could impact decision making at baseline. During follow-up, the percentage LDL-C reduction is the focus, and, therefore, differential influences on LDL-C measurement at baseline and follow-up could alter preventive therapy.

To prevent events, there must be events. That is, the probability of an event must be sufficiently high to make a relative decrease in that probability worthwhile.10 Two patients, both of whom could be considered for a high-intensity statin due to elevated LDL-C levels, may have markedly different absolute risks (e.g. 20% vs. 2%) due to other risk factors. In this situation, an RRR of 50% would translate into absolute risk reductions (ARR) of 10% and 1%, respectively. This difference in ARR leads to a number needed to treat (NNT) that is 10X higher for the patient with an original 2% absolute risk (1/.1= 10 vs. 1/.01=100). Herein lies the importance of the long-term prevention paradigm of matching cholesterol therapy with those at the highest absolute risk.

The new ACC/AHA cholesterol treatment guidelines value the art of medicine by allowing for individualizing primary prevention on the basis of shared decision making between the patient and clinician. This is important to mention because there is no way to answer this question, which is heavily tied to the changes reflected in the new guidelines, without practicing similarly to the way the guideline authors anticipated: with a personalized approach for each patient. As seen in the examples above, both LDL-C measurements and absolute risk assessments are important and provide complimentary information. More research is needed, but based on the best available evidence it appears that a balance of estimating risk (ARR) and measuring LDL-C (RRR) is appropriate.


  1. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
  2. Stone NJ, Robinson J, 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;63:2889-934.
  3. Stone NJ, Robinson JG, Lichtenstein AH, et al., on behalf of the 2013 ACC/AHA Cholesterol Guideline Panel. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med 2014;160:339-43.
  4. Martin, SS, Blumenthal, RS. Concepts and controversies: the 2013 American College of Cardiology/American Heart Association risk assessment and cholesterol treatment guidelines. Ann Intern Med 2014;160:356-59.
  5. Martin SS, Abd TT, Jones SR, et al. 2013 American cholesterol treatment guideline: what was done well and what could be done better. J Am Coll Cardiol 2014;63:2675-8.
  6. Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, et al. 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;376:1670-81.
  7. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013;310:2061-8.
  8. 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;18:499-502.
  9. Miller WG, Waymack PP, Anderson FP, Ethridge SF, Jayne EC. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem 2002;48:489-98.
  10. Martin SS, Blaha MJ, Blankstein R, et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the multi-ethnic study of atherosclerosis. Circulation 2014; 129:77-86.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Algorithms, American Heart Association, Cholesterol, Cholesterol, LDL, Decision Making, Dyslipidemias, Fellowships and Scholarships, Female, Follow-Up Studies, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Lipoproteins, LDL, Nigeria, Numbers Needed To Treat, Primary Prevention, Probability, Risk, Risk Assessment, Risk Factors, Seasons, Triglycerides, United States

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