LDL-C or apoB as the Best Target for Reducing Coronary Heart Disease

Should Apob be Implemented into Clinical Practice?

Helena Vaverkova

Disclosures

Clin Lipidology. 2011;6(1):35-48. 

In This Article

Review of Interventional Studies

On-treatment LDL-C has Little Prognostic Value while apoB Predicts the Clinical Outcomes

Statins have proven effective for both the primary and secondary prevention of CVD in nondiabetic and diabetic populations.[3,4] Several interventional studies have demonstrated that on-treatment LDL-C has little prognostic value while apoB predicts the clinical outcomes well.[45–48] In the primary prevention Air Force/Texas Coronary Artery Prevention Study (AFCAPS/TexCAPS), treatment with lovastatin resulted in a 37% reduction in the risk of the first acute major coronary event. Only on-treatment apoB and the apoB:apoA-I ratio were predictive of subsequent risk, while LDL-C was not.[45] In the secondary prevention study Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID), pravastatin significantly reduced both mortality and CHD events in patients with known CHD. In this trial, on-study apoB was a stronger predictor of the risk of CHD events than LDL-C and the best single predictor of the pravastatin treatment effect.[46]

Recently, a post hoc analysis was performed that combined data from two randomized secondary prevention clinical trials (Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL]) with a total of 18,889 patients.[48] Both of these studies compared treatment with standard doses of statins (atorvastatin 10 mg and simvastatin 20–40 mg, respectively) versus intensive statin treatment (atorvastatin 80 mg in both studies). In models that included LDL-C, only non-HDL-C and apoB were positively associated with the cardiovascular outcome, whereas the positive relationship with LDL-C was lost. On-treatment mean levels of TGs in both treatment groups of the TNT and IDEAL trials were low (116.6 ± 66.3 and 156.0 ± 86.5 mg/dl, respectively).

Among the ratios that included both proatherogenic and antiatherogenic lipoprotein measurements, apoB:apoA-I showed the strongest relationship with a primary outcome (major cardiovascular events).[48]

Statins Lower LDL-C & non-HDL-C to a Greater Extent than apoB & in Lower Population Percentile Levels

Statin trials in which LDL-C, non-HDL-C and apoB have been measured have demonstrated that the percentage reduction in LDL-C and non-HDL-C concentration is greater than for apoB. For example, in the Collaborative Atorvastatin Diabetes Study (CARDS), atorvastatin treatment reduced LDL-C concentration by a mean of 40.9%, whereas atorvastatin treatment decreased the non-HDL-C by 38.1% and apoB by 24.3%, compared with a placebo.[49,50] Similar results were obtained in many other studies (reviewed in[51]). In an analysis of 11 studies of LDL-lowering therapy, LDL-C, non-HDL-C and apoB were reduced on average by 42.1, 39.6 and 33.1%, respectively, resulting in a lowering of these three parameters to the 21st, the 29th and 55th percentile of the population, respectively.[51] Thus, it is evident that the lowering of apoB was not satisfactory, and the treatment left the patients in these trials at high risk.

Achievement of LDL-C, non-HDL-C & apoB Goals in Interventional Studies

The last version of the American NCEP ATP III guidelines recommends an LDL-C target of less than 100 mg/dl for high-risk subjects and an optional LDL-C target of less than 70 mg/dl for very-high-risk patients.[1] These guidelines do not recommend apoB for the evaluation of risk or monitoring therapy. ATP III identifies the sum of LDL-C plus VLDL-C (non-HDL-C [total cholesterol minus HDL-C]) as a secondary target of therapy in persons with high TG levels (≥200 mg/dl). The goal for non-HDL-C in persons with high TGs was set at 30 mg/dl (0.8 mmol/l) higher than that for LDL-C. For the majority of people who have lower TG levels, ATP III considers the LDL-C goal alone to be sufficient as it contains the bulk of atherogenic cholesterol.[18] In the European guidelines, neither non-HDL-C nor apoB are a part of the general recommendations.[2]

Treatment goals for apoB have been suggested by several groups of experts: in a report of 30 experts/ten countries panel receommending apoB levels of less than 90 mg/dl for high-risk patients and less than 80 mg/dl for very-high-risk patients;[52] in a statement of the American Diabetes Association (ADA)/American College of Cardiology Foundation (ACCF) recommending comparable targets for patients with cardiometabolic risk;[53] and more recently, by an AACC statement recommending an apoB goal of less than 80 mg/dl for both high- and very-high-risk patients.[31] Additional apoB goals have also been accepted in some national guidelines such as in Canada[54,55] and in the Czech Republic.[56]

Several lipid-lowering studies have demonstrated that a large proportion of patients who achieve their LDL-C or non-HDL-C goals remain above the treatment target for apoB, which represents an important treatment gap.[57]

Stein et al. published a study in which they assessed attainment of the LDL-C, non-HDL-C and apoB goals in a large database of patients with combined hyperlipidemia, with 22,000 samples from various clinical trials in which TGs, HDL-C, LDL-C, non-HDL-C and apoB were available in the same sample.[58] These patients were mainly on statin monotherapy and included all the statins and all of the doses that were currently available. The data were analyzed according to baseline TG levels of less than 200 mg/dl and 200–500 mg/dl. In patients with baseline TG levels of less than 200 mg/dl, approximately 60% of patients attained their LDL-C and non-HDL-C goals (<100 and <130 mg/dl, respectively). However, only 30% (half of those patients) attained their apoB target of less than 90 mg/dl. In patients with baseline TG levels of 200–500 mg/dl, although the number of patients obtaining an LDL-C goal of less than 100 mg/dl still remained approximately 60%, the number of subjects attaining an apoB goal of less than 90 mg/dl has decreased from 30 to only 17% and the number of patients left with very high apoB levels of greater than or equal to 120 mg/dl increased to nearly 50%. Even in those who reached LDL-C levels of less than or equal to 70 mg/dl, 30% of them did not attain their apoB goal of less than 90 mg/dl.

Very similar results were obtained in several other studies published prior to this study[59] and more recently.[60,61]

All of the aforementioned studies demonstrate that many patients, especially those with high TGs or impaired glucose tolerance, who reach LDL-C levels of less than 100 mg/dl or non-HDL-C levels of less than 130 mg/dl, have not achieved their correspondingly low apoB treatment targets of less than 90 mg/dl.[58–61] On the other hand, when on-treatment apoB is less than 90 mg/dl, virtually all patients can also reach the aforementioned LDL-C and non-HDL-C goals.

The potential importance of LDL particle concentrations in patients with optimal LDL-C control is supported by the study of Bayturan et al..[62] This study analyzed determinants of coronary plaque progression in patients with CHD who underwent serial intravascular ultrasound examination (analysis of seven intravascular ultrasound studies). In patients with on-treatment levels of LDL-C of less than or equal to 70 mg/dl, progressors demonstrated smaller decreases in apoB levels (p = 0.001) and reduced increases in HDL-C (p = 0.01).

The importance of high numbers of atherogenic particles, despite low LDL-C levels, is further supported by the results of a large, community-based study[10] that showed that low LDL particle numbers (as measured by NMR) were a better index of low CVD risk than low LDL-C.

Sniderman[57] and other experts[31] believe that apoB targets should be set so that apoB levels are equivalent to those for LDL-C in terms of population percentile levels. According to data from the Framingham Offspring Study (FOS), an LDL-C concentration of 100 mg/dl is equivalent to the 20th percentile, and the corresponding level of apoB would be 80 mg/dl (0.8 g/l).[63] However, only a small subset of patients is able to reach such a low level of apoB. Thus, it represents a challenge for using a combination therapy and for discovering new LDL-lowering drugs.

ApoB levels corresponding to the LDL-C target of less than 130 mg/dl (50th population percentile) would be apoB levels of less than 100 mg/dl, and levels corresponding to the LDL-C goal of less than 160 mg/dl (80th population percentile) would be apoB levels of approximately less than 120 mg/dl. Nevertheless, the equivalent values are only approximate as they will vary depending on the population studied and the laboratory performing the analysis.

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