Evolving Evidence, Conflicting Interpretations

Controversies surrounding the 2013 ACC/AHA Guideline for lipid management include:

  • The ACC/AHA risk threshold of 7.5% 10-year risk is not universally recognized as the best threshold. For example, the National Institute for Health and Clinical Excellence in the United Kingdom (NICE) recommends using 10-year risk > 20% (DynaMed,2013).
  • The 2013 ACC/AHA CV risk calculator may overestimate cardiovascular risk, contain an error, and/or be less reliable in certain populations (Lancet 2013; DeFillipis, 2015). The American Association of Clinical Endocrinologists, in large part due to the inaccurate calculator, did not endorse the 2013 guideline (AACE, December 2013). Other calculators may provide better risk estimates.
  • Primary care organizations (e.g. AAFP, ACP) were not invited to participate in the 2013 guidelines.
  • 20 of 46 recommendations are graded “expert opinion,” rather than strong evidence based on RCTs (AAFP, 2013).
  • 6 of 15 panelists of the guideline reported having recent or current ties to drug makers that already sell or are developing cholesterol medications (Forbes, 2013)
  • 1 of 2 co-chairs of the new guideline panel has ties to a drug maker, which ignores Institute of Medicine recommendations about managing conflicts of interest on panels (Forbes, 2013).


  • Most significantly, the debate about whether to use target statin doses or target LDL-levels remains debated in the literature and among individual providers.

Those who agree with the 2013 guidelines using target dosing, cite the weak observational evidence and/or post-hoc analyses of controlled studies without hard clinical outcomes (e.g., myocardial infarction) and the ris for drug-drug interactions with higher doses (Hayward et al, 2012; Downs et al, 2015). In 2015 the VA re-affirmed the 2013 guidelines as best practice in the care of veterans, a populations with an overall high CV risk.

Nevertheless, many remain deeply committed to LDL targets. The industry-sponsored trial, IMPROVE-IT, published in the NEJM in 2015 has re-ignited discussions about using LDL target levels. The study, in high-risk patients, demonstrated that combination therapy with ezetimibe added to a statin provided a 2% benefit in a composite outcome (combining death, stroke, hospitalization, etc.) but no all-cause mortality benefit over statin alone. The slightly better composite outcome was associated with a somewhat lower LDL, so this has been put forward as justification for reintroducing non-statin therapy if not using LDL targets as a goal in themselves. LDL targets also remain the favored marketing strategy for pharmaceutical companies (Nature, 2013).

Additional research is needed on many actively debated lipid-related topics:

In addition to the above issues, there are other aspects of cholesterol management with little RCT data behind them. These topics may become the focus of future studies and guidelines:

  1. Treatment of hypertriglyceridemia
  2. Use of non-HDL in treatment decision making
  3. Role of Apo B, Lp(a) or LDL particles in treatment decision making
  4. Using noninvasive imaging (e.g. cardiac CT) for refining risk estimates to guide treatment
  5. The role of lifetime (as opposed to 10 yr) ASCVD risk to inform treatment decisions.
  6. Efficacy of statins in subgroups (e.g., heart failure, on renal replacement therapy, HIV positive, or solid organ transplants).
  7. Long term effects of statin-induced new onset diabetes.
  8. Role of pharmacogenetic testing
  9. Investigations, post-marketing surveillance, and cost-effectiveness studies of newer lipid agents such as the injectable PCSK9 inhibitors are under way.


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