Specialty Corner: A Guide for Clinicians to Escape the Tyranny of Guidelines

In keeping with the theme of this issue of the LipidSpin, this Specialty Corner is devoted to advice for the practicing clinician who has to make daily decisions on how best to protect his/her patients from cardiovascular disease.

It seems since the 2013 publication of the American College of Cardiology/ American Heart Association (ACC/AHA) guidelines, we have been engaged in countless discussions about them, either for or against, and all of the reasons to support each view. Well, the world is a complicated place, because we really have at least six new guidelines from which to pick (Figure 1). However, despite all these guidelines, the common thread that joins them all is reduction of low-density lipoprotein cholesterol (LDL-C) to reduce and prevent events. We have to make every clinical decision with this in mind. This is not meant to ignore other important factors, such as smoking, hypertension, and diabetes. My comments as a lipidologist are focused the same as all the lipid guidelines — on how to impact LDL-C. I also plan to further address my belief that apolipoprotein B (ApoB) and low-density lipoprotein particle number (LDL-P) are more useful indices to measure to improve on LDL-C-centric thinking.

A quote from the most talked about guideline — the ACC/AHA guidelines — states, “The expert panel acknowledges that our process did not provide for a comprehensive approach to the detection, evaluation, and treatment of lipid disorders…”¹ As clinicians doing the heavy lifting every day for our patients at risk, who among us does not want a comprehensive approach, and the freedom to treat our individual patients’ lipid disorder with more than just a moderate-or high-intensity statin? We cannot ignore residual dyslipidemia because one group of experts couldn’t find randomized controlled trials (RCTs) to support its treatment.

I believe therapy goals are as important for lipids as they are for blood pressure and glucose control. Despite the inability to prove that lowering hemoglobin A1c (HbA1c) prevents events, most clinicians still have therapy goals. Despite having no evidence-based medicine for our individual favorite therapy using three or more antihypertensive agents, most clinicians have a target blood pressure range they try to achieve. Accordingly, I also believe in goals of lipid therapy. In an excellent editorial about guidelines, Dr. Henry Ginsberg reviews for us the list of RCTs that employed goals of therapy in both primary and secondary prevention.² We also know from the Cholesterol Treatment Trialist study that lower is better, regardless of where you start.³ We have data from bile acid binding resins,⁴ niacin,⁵ and ezetimibe⁶ trials that all demonstrate that lowering LDL-C with non-statins reduces events. It is my recommendation to my colleagues that we use the guidelines as guidance, not as commandments. Where the guidelines are able to provide evidence- based data that applies to our individual patient, they clearly make sense. What does not make sense is doing nothing in the absence of evidence-based medicine that has not yet been elucidated for my high-risk patient with complex dyslipidemia.

Therefore, I recommend that all clinicians understand what non-statin drugs such as ezetimibe, niacin, bile acid binding resins, and even fibrates do, and how. Clinicians should understand lipid metabolic pathways to gain an understanding of how triglycerides influence the numbers we see on our test results, as I outlined in an earlier LipidSpin article.⁷ We need to understand how the new class of proprotein convertase subtilisin/kexin type 9 (PCSK9) therapies work, when to employ them, and what to expect from them. Only armed with that comprehensive knowledge can we move beyond the tyranny of guidelines, take what we need from them, and then treat the individual patient to address each and every risk by which that patient is confronted.

The constraints of RCTs make it virtually impossible to detect the changes in the progression of atherosclerotic vascular disease that occur in timeframes longer than the trial. We all realize that atherosclerosis is a cumulative phenomenon that manifests over the life of our patient. The key is to know when and in whom to intervene, as well as to quantify the goals and success of our intervention.

I, for one, endorse the National Lipid Association Recommendations  as a practical and clinically meaningful guide by which to assess risk and to assist the clinician in knowing when to intervene.⁸  They also quantify therapy goals.

Now that we have discussed moving beyond the constraints of therapy guidelines, I would like to address what I believe are the most accurate methods of determining our lipid status. The more accurately we can measure dyslipidemia, the more accurately we can treat it.

In clinical practice, we often are confronted by a significantly variable response to lipid therapy.⁹ We also are confronted by so-called residual dyslipidemia when our best statin therapy fails to get our patient to goal. How should we proceed when confronted with this scenario?

My recommendations in this area begin first by most accurately determining the status of the patient’s dyslipidemia. The most recent NLA Recommendations address this issue by setting both non- HDL-C goals and LDL-C goals.⁸ These guidelines say that non-HDL-C is superior to LDL-C, with ApoB as a secondary target. This approach also is supported by the European Atherosclerosis Society,¹⁰ Canadian Atherosclerosis Society,¹¹ and International Atherosclerosis Society¹² guidelines.

Back to the premise that we only take from guidelines what they can prove to us. To consider this, we must first consider the concept of discordance. This term refers to individuals in whom other measures of atherogenic particles are inconsistent with LDL-C measurements. The most classic example of discordance would be a patient who is in the 50th  percentile by LDL-C measurement, but in a significantly different percentile by measuring Apo B or LDL-P. This is a painfully simplified example, but it makes the point that some of us transport our lipids differently from others, and may be at more or less risk than LDL-C measurements imply. Simply considering the weight of our cholesterol per deciliter of plasma is, in my view, not always as accurate as I would like. To this point, there also are multiple clinical trials that were not included in ACC/AHA guidelines that demonstrated the superiority of measurements of ApoB and non-HDL-C over LDL-C in patients that demonstrated such discordance. This list includes the Quebec Cardiovascular Study, the Framingham Offspring Study, Interheart, Women’s Health study, and MESA.¹³

This is of critical importance to the practicing clinician, because the patients most likely to be affected by discordance are ones we generally consider to be higher-risk patients — diabetics and those with insulin resistance.¹⁴ If my clinical practice resembles the practices of my colleagues, I would submit that diabetics and patients with insulin resistance are sitting in our waiting rooms every day of our practice lives. What an opportunity we have to recognize the potential severity of their dyslipidemia — if we only take a moment to think about testing beyond LDL-C and consider residual dyslipidemia.

In summary, our clinical practices provide us both the opportunity and the obligation to do the very best for our patients. I believe clinicians and patients are best served when we clinically integrate the suggestions that guidelines provide with our knowledge of pharmacology and physiology — and of our patients trusting us to palliate their risks.

Disclosure Statement: Dr. Lillo was on the speakers bureau for Amgen, Sanofi-Regeneron, Merck, Amarin, Kowa, and Actavis. He also participated in research trials for Amgen, Merck, Abbvie, Ironwood, Pearl, Pfizer, Theravance, and Daichi-Sankyo.

References are listed on page 35.