HJAR Nov/Dec 2023

CHANGING THE CARE: HEART DISEASE & CHOLESTEROL 26 NOV / DEC 2023 I  HEALTHCARE JOURNAL OF ARKANSAS   them. Indeed, this fear illustrates the power of the human mind through something known as the “nocebo effect.” The nocebo effect is said to occur when negative expectations of the patient regarding a treatment cause the treatment to have a more negative effect than it otherwise would have. For example, when a patient anticipates a side effect of a medica- tion, they can experience that effect even if the “medication” is actually an inert substance. The nocebo effect has been studied and pub- lished with the statins. In studies where patients reported previous muscle aches following ini- tiation of a statin, but who were then later re-challenged with a placebo or inert “sugar pill” that they thought was a statin, these pa- tients again reported the same muscle aches. Overcoming these negative expectations among patients requires two things I’ve writ- ten about in prior articles: time and trust. It takes time to sit there with them and explain the nocebo effect, and time is not something that primary care providers have enough of in the prevailing time-limited, volume-driven models of standard primary care. It also takes time to build a trusting relationship, and it takes empathy to earn patient trust. If we doctors expect that patients should just trust us and do what we recommend because of our education and advanced degrees, then we fundamentally don’t understand the na- ture of trust. If a patient chooses to not take a statin because their neighbor’s cousin had “bad muscle cramps and couldn’t walk after taking Lipitor,” it just means they trust their neighbor more than their doctor. Reassurance from a clinician they trust about the very low risk of muscle aches, along with education about the nocebo effect, is typically all that is needed to get patients to at least try a statin. Statins are important because they have been conclusively shown to reduce major cardiovas- cular events in patients at high risk of heart disease and because they save lives. Not only do they powerfully lower LDL, but they also have anti-inflammatory and antioxidant prop- erties that help stabilize vascular endothelium in diseased vessels, thus reducing the risk of atherosclerotic plaque rupture. Logically, all good clinicians know of these beneficial prop- erties, but simply knowing the information and telling our patients to take a statin is not enough. The art of convincing them of these benefits involves taking the time to build an empathetic, collaborative, trusting relationship where we have the time to fully explore their fears, uncertainties, and doubts about statins. It is also a classic example of implementing an “upstream” solution — statin therapy — to help prevent atherosclerotic plaque rup- ture over the economically more favorable “downstream” solution of placing the coronary stent once the plaque has already ruptured and the vessel is now completely occluded. Once we have successfully gotten a patient on statin therapy, the next thing is to be mind- ful of those very rare cases where muscle tox- icity does occur, something easily monitored for by checking a muscle enzyme known as creatine phosphokinase (CPK) if patients re- ally do experience muscle aches. Significant elevations do warrant statin discontinuation, but that only occurs in less than 2% of patients. Just as important as monitoring for these rare toxicities is to monitor for therapeutic effec- tiveness. When HealthPartners rolled out their optimal diabetes measure, the medical litera- ture at the time favored targeted LDL goals of <100 in patients on statins. Guidelines moved away from these targeted goals in subsequent years, favoring instead an approach based on the intensity of statin therapy. Moderate intensity statins were recommended when a goal of lowering LDL cholesterol by 30-49% was favored, and high intensity statins were recommended when 50% reductions were called for. For patients with known atheroscle- rotic vascular disease, a targeted LDL goal of <70 is still highly recommended. I suspect we may see a return of targeted LDL lowering for all patients, however, because studies of the benefits of rigorous cholesterol lowering show that when it comes to LDL, lower is better. Indeed, combination therapy will likely reach the same level of endorsement for lipid-lower- ing therapy as for blood pressure and diabetes. We know that most patients with hypertension require two to three anti-hypertensive medica- tions to achieve optimal blood pressure control. Likewise, most patients with diabetes require more than one anti-diabetic agent to achieve adequate glycemic control and optimize their overall cardiovascular risk. The same is prob- ably also true for cholesterol therapy. LDL levels >190 are extremely elevated, and adult patients with that magnitude of elevation need aggres- sive lowering no matter how young they are. I suspect we need to be more aggressive at get- ting LDL <100 in almost everyone and certainly <70 in patients with known vascular disease. Doing so very likely requires maximally toler- ated doses of statins plus at least one or even two additional cholesterol-lowering agents. There are other lipid-lowering agents that are currently available and supported by evi- dence with more on the horizon. The first of these, ezetimibe (Zetia) is commonly added to statins in cases where a goal LDL of < 70 is necessary but not achieved with statins alone. Ezetimibe can lower LDL by almost 20% and is very well tolerated. Often, the additional 20% or so reduction may be enough to achieve the targeted goal, but in cases where it isn’t, the PCSK9 (proprotein convertase subtilisin/ kexin type 9) inhibitors may become neces- sary, especially in patients with known vascular disease. The PCSK9 inhibitors — evolocumab (Repatha) and alirocumab (Praluent) — have mostly been prescribed by cardiologists in the past but should likely increasingly be pre- scribed by primary care as we become progres- sively better versed in optimal medical therapy. Over-the-counter fish oil supplements confer little to no benefit because the concentration of fish oil they contain is inadequate. However, Icosapent ethyl (Vascepa) is a highly purified fish oil that is indicated in patients with persis- tently elevated triglyceride levels despite statin therapy and either known vascular disease, diabetes, or age >50 plus at least one other risk factor for atherosclerotic vascular disease. Fibrates, like the drug fenofibrate, should re- ally be reserved for severe elevations of tri- glycerides (at least >500 and especially >1000). The new kids on the block and advanced lipidology In those rare cases where statin intolerance does occur, one of the newest kids on the block is bempedoic acid (Nexletol), which can be safely prescribed in combination with ezeti- mibe or PCSK9 inhibitors. Like ezetimibe, it has the potential to lower LDL by nearly 20%.