The correct answer is: D) Any of the above are reasonable approaches.

This high-risk statin-treated patient is an example of the residual risk that we see in everyday practice. One key aspect to consider is the discordance between his lipid values. Long-term, high-potency statin therapy has reduced his LDL-C and non HDL-C to acceptable levels (per ATP III guidelines).¹ Despite this, he has had a recurrent coronary event. From a population perspective, although his LDL-C places him at the 15th percentile, his non-HDL-C is at the 25th percentile and his apoB is between the 30th and 40th percentile.^2,3 This type of discordance is often typical in diabetic subjects or those with features of the metabolic syndrome.⁴ Furthermore, LDL-C calculations (Friedewald-calculations) at TG levels above 150 mg/dL often underestimate the true LDL-C.⁵ Considering potential discordance and underestimation, whereas the LDL-C in this case may be reassuring to some, we view it cautiously.

While randomized controlled trial outcomes evidence is presently lacking for lipid-lowering therapies in addition to statin treatment, strong biological and epidemiological data support targeting a lower apoB.⁶ Atherosclerosis is fundamentally triggered by the retention of atherogenic particles within the arterial wall.⁷ Every potentially atherogenic particle contains one surface copy of apoB, which confers atherogenicity to the particle. Cholesterol concentrations within apoB-containing particles, most notably LDL-C or non HDL-C, have long been the clinical standard for assessment of risk and therapeutic targets. However, since the cholesterol content within these particles can vary (i.e. small, dense LDLs carry less cholesterol per particle), apoB consistently outperforms these markers of atherogenic particle burden for risk prediction, particularly when there is discordance.⁸

For patients with atherosclerotic CVD, the 2013 ACC/AHA cholesterol guidelines only specifically recommend high-potency statin therapy (choice A).^9,10 These guidelines are best viewed as a starting point for risk discussion and shared decision-making with your patient, which should include the fact that the patient's residual risk is not zero. Importantly, the guidelines adhered to the strictest evidence base for its recommendations (the highest-quality randomized controlled trials [RCTs] only). The new guidelines shifted from targeting cholesterol levels to suggesting a 50% reduction in LDL-C for high risk subjects through high potency statin use. However, the new guidelines do not address changes to therapy in the setting of recurrent events in those who have been on guideline directed therapy for years, such as this patient. Any management beyond the guideline recommendations should be based on the caregiver's best interpretation of the available data.

Since statins more effectively lower LDL-C and non-HDL-C compared with apoB¹¹, the addition of apoB-reducing therapies (choices B and C) are a reasonable consideration for this patient seeking further options to potentially reduce his risk. Ezetimibe and colesevelam are safe medications that lead to further reductions in apoB when added to statins.^12,13 Due to more favorable tolerability, we generally use ezetimibe as our first add-on therapy to achieve greater apoB reductions. We eagerly await the results of the ongoing IMPROVE-IT trial (NCT00202878) testing whether the addition of ezetimibe to statin therapy reduces CVD events.¹⁴ Bile acid sequestrants have already been proven to effectively reduce CVD as monotherapy¹⁵. Recent disappointing results from trials testing the addition of niacin preparations to statin therapy have created doubt over the role of niacin therapy.^16,17 However, it is important to recognize that apoB levels were nearly equivalent in the two treatment arms of AIM-HIGH, suggesting a possible etiology for equivalent outcomes.¹⁸ Similar to other add-on agents, we view niacin as an apoB-reducing therapy that may still be considered in those with residually elevated apoB on maximal statin therapy.

Based on post-hoc analyses of statin trials, the ACC/ADA statement in 2008 suggested a target apoB of less than 80 mg/dL in high-risk subjects.¹⁹ Recent lipid guidelines from the Canadian Cardiovascular Society also suggest an apoB of less than 80 mg/dL for high-risk subjects.²⁰ Others have argued for a lower target apoB since the equivalent percentile in the general population for an LDL-C of 70 corresponds to an apoB of 60 mg/dL.³ In our experience, an apoB target of 60 mg/dL often requires multiple lipid-lowering therapies. Recognizing the difficulty of attaining an apoB <60 mg/dL,²¹ we reserve consideration of this aggressive target for those at highest risk for recurrent CVD, such as this patient.

In our practice, the patient who is making the appropriate lifestyle modifications and is already on high-potency statin with discordant apoB levels is an ideal candidate for further apoB reduction. We also target apoB more aggressively in subjects with elevated lipoprotein (a) [Lp(a)], a marker that European guidelines and the National Lipid Association consider reasonable to measure in those with high CVD risk or a family history of premature CVD.^22,23 Importantly, in contrast to LDL-C (often calculated), worldwide standards are in place for apoB measurements through the WHO and the CDC, helping to ensure credibility and reproducibility of the results.²⁴ We have reduced the cost of an apoB measurement to $20 by incorporating the simple table-top assay into our clinical lab's throughput.

In discussions with our patients, we emphasize the lack of RCT data for both add-on therapy to statins and treating to a target, advise of possible side effects, and help the patient come to a decision that he or she is comfortable with based on our interpretation of sound scientific evidence. In practice, guidelines are the necessary starting point for risk reduction, but further emerging science can help tailor therapy in motivated patients who remain at risk.

References

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