Navigating the Unknown in The World of Lipid Management – Where are We Now?

Atherosclerosis may begin in childhood with an initial lesion that progresses into fatty streaks. Then, as we age into our 20s and 30s, those lesions may become more complex type III and type IV atheromas^1-5. In our fourth and fifth decades, those may develop the fibroatheromas and complicated lesions that may eventually lead to a myocardial infarction or stroke.

Given what we already know about the progression of atherosclerosis and the prevalence of coronary artery disease (CAD), it makes sense to begin primary prevention before the fourth decade⁶. However, because of a lack of data addressing primary prevention in those younger than age 40 who do not have known atherosclerotic cardiovascular disease (ASCVD) but are at elevated risk, guidelines have fallen short on primary prevention protocol. For example, while the 2013 lipid guidelines from the American College of Cardiology (ACC) recommend that patients with an elevated 10-year risk be started on a statin⁷, the recommendation applies only to those age 40 and older whose 10-year risk are calculated by the ASCVD risk calculator.

While the recommendations do endorse starting high-intensity statins (for example, atorvastatin or rosuvastatin) in patients older than 21 years with LDL-C levels of 190 mg/dL or higher, recommendations remain unclear for those who are 21 to 40 years old and have LDL-C levels between 70-189 mg/dL—regardless of their lifetime risk. In fact, the risk calculator used to calculate lifetime risk and 10-year risk has been a source of controversy in and of itself⁸.

There was hope that the 2016 US Preventive Services Task Force (USPSTF) recommendations on statin use for the primary prevention of cardiovascular disease⁹, published just this month, would clarify these questions. Instead, the new recommendations seem to merely reiterate the same conclusions found in the 2013 ACC guidelines. Namely, in the 2016 recommendations, the USPSTF concluded that for patients 21 to 39 years old, there was insufficient evidence (i.e., no studies evaluating specifically primary prevention in this age group) that a particular therapy — such as statins — was effective. Physicians are thus left to their own clinical judgment, with little evidence or consensus-based support to justify their decisions.

Curiously, despite limited data for primary prevention in high-risk patients older than age 40, the task force does recommended statin therapy for this group. However, there may have been insufficient evidence for the task force to come to that conclusion. Redberg, et al. points out that studies evaluating secondary prevention were not excluded from the review on primary prevention, and that the authors did not have access to primary data from industry-supported clinical trials¹⁰. Redberg, et al. also suggest that when the available data is looked at more objectively, statin therapy would prevent only two myocardial infarctions out of 100 people treated, and that 5-20 of those 100 patients will experience significant side effects from the drugs¹⁰. The number needed to treat has long been a concern among those who oppose prescribing statins to, literally, everyone with a heart.

Among patients who do have clear indications for statin therapy, the controversy over the ACC’s shift from LDL targets towards statin intensity and 50% LDL reduction has left clinicians at a loss as to how to monitor and titrate statins. The shift from LDL targets is based on several large randomized controlled trials that showed that:

• Statins significantly reduce cardiovascular events and mortality in various populations;

• Higher intensity statins may be more effective than lower intensity statins at reducing those clinical outcomes;

• Maximal-dose high-intensity statins have been associated with plaque regression in patients with established CAD^7-11.

There was little to support LDL targets previously set by the ATP III, and so the ACC decided to eliminate the LDL target altogether and to advise clinicians to start moderate or high-intensity statins based on risk^7,12. It was thought that this change would simplify statin dosing and eliminate redundant blood work¹³. However, the disagreements that arose between cardiologists and lipid specialists around the LDL issue have left primary care providers struggling to grasp what exactly they should do for their patients. In fact, 50% of primary care physicians were unable to identify the four statin-benefit groups defined in the 2013 guidelines, and most PCPs were not aware of the new 10-year–risk threshold for starting statin therapy¹⁴. Therefore, it is no surprise that 32% of statin-eligible patients—based on the 2013 guidelines—in the NCDR PINNACLE registry were not receiving statins, despite the new guidelines¹⁵.

Anecdotally, many of the highest-risk patients who have established CAD, and should be on maximally-dosed high-intensity statin therapy, are often initiated or kept on moderate-intensity statins at suboptimal doses by their primary care providers. The reasons for this sub-maximal therapy are unclear. Fear of statin-induced myopathy¹⁶ likely plays a role. But there also may be an assumption that higher-intensity statins don’t offer any additional survival benefit above moderate doses¹⁷.