Clinicians and patients may find recent studies relevant to decisions about lipid-lowering therapy to be perplexing. There are now, for the first time, 3 evidence-based options to modify atherosclerotic cardiovascular disease risk via lipid-lowering medications. With new information emerging, recent guidelines aging, and decisions needing to be made, this is an opportune time to review lipid-lowering therapy in the age of increasing evidence-based choice. The focus in this Viewpoint is on typical patients, not those with extreme phenotypes.
When the American College of Cardiology/American Heart Association (ACC/AHA) published the Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults1 in 2013, only the use of statins, among lipid-lowering medications, was strongly supported by evidence of improved patient outcomes. The guideline’s emphasis on statins for secondary prevention and for individuals at higher risk of disease was reinforced by a recent report that estimated the treatment of 10 000 patients for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 hemorrhagic strokes while averting about 1000 events among those with preexisting disease, and 500 among those with elevated risk but without preexisting disease.2 Despite this evidence, uptake of statins remains suboptimal in the United States and elsewhere and offers an opportunity for improvement. Moreover, despite the available research, evidence is lacking about the comparative effectiveness and safety of particular statins for specific individuals.3
The groundbreaking pivot of the ACC/AHA Guideline from targets to the use of evidence-based treatments based on risk was not a repudiation of the lipid hypothesis, but rather an effort to align recommendations with evidence. The trials had tested the effect of specific drug regimens on risk, not a strategy of treating to a target-level agnostic to drug. Moreover, the trial evidence proved that not all drugs that favorably modify lipid levels improve patient outcomes, perhaps because of their negative pleiotropic effects.
More evidence-based options have emerged for secondary prevention. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)4 reported that adding ezetimibe to effective statin therapy in stable patients who experienced an acute coronary syndrome reduced low-density lipoprotein cholesterol (LDL-C) from 70 mg/dL to 54 mg/dL (to convert LDL-C from mg/dL to mmol/L, multiply by 0.0259), and reduced risk of atherosclerotic cardiovascular disease outcome at 7 years from 34.7% to 32.7%. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial5 reported that the addition of evolocumab, a proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor, to effective statin therapy reduced LDL-C from 92 mg/dL to 30 mg/dL and decreased the composite cardiovascular outcome over 2.2 years from 11.3% to 9.8%, a 15% relative reduction. Of note, both drugs were only tested in high-risk individuals.
There are some caveats to the new evidence. Although no significant safety signals emerged with either drug, some consider the benefits to be relatively small. The US Food and Drug Administration determined in 2016 that the IMPROVE-IT trial was insufficient to expand the label for ezetimibe to include reducing the risk of myocardial infarction and stroke. Ezetimibe, nevertheless, is now available as a generic and is inexpensive. But evolocumab is costly, and its value is under debate. Also, evolocumab was not tested against a statin-plus-ezetimibe combination, which might currently be the appropriate comparator. For most patients, both drugs will be second-line and third-line options. Meanwhile, physicians await evidence regarding other alternatives, such as alirocumab, anacetrapib, icosapent ethyl, and RNA interference agents, to see if they will join the evidence-based outcomes options.
New evidence has suggested that niacin is not effective. The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial6 reported that among 25 673 high-risk individuals with established atherosclerotic cardiovascular disease, adding extended-release niacin in combination with laropiprant (used to mitigate the discomfort of niacin-generated flushing) to effective statin-based LDL-C–lowering treatment failed to realize any clinical benefit. The niacin combination increased the risk of adverse events, reduced quality-of-life–adjusted survival, and increased costs.6
Lipid-lowering therapy for primary prevention, that is, for patients with no previous cardiovascular event, can be a complex decision. Risk assessment is a linchpin that guides decision making for primary prevention. Individuals with the highest risk have the most to gain. Meanwhile, there are debates about which risk calculator is best for which patients. Studies show some differences, but, from the patient’s perspective, the differences among them likely seem small and only important when guidelines suggest there is a specific artificial threshold above which treatment is recommended. What is increasingly clear is that nearly half of individuals without prior disease who are identified as being at high risk of disease by conventional risk scores may be reclassified as having much lower risk in the absence of coronary artery calcium.7
In addition, shared decision making is particularly important when the risks and costs of an intervention are immediate and the benefits are in the future. Moreover, patients vary considerably in their views about what amount of benefit from a prevention drug is meaningful enough to merit taking a pill every day. Nevertheless, despite the importance of shared decision making, as noted in the ACC/AHA guideline, few effective tools exist. In particular, there remains a need for better point-of-care algorithms that individualize estimates of risks and benefits and that could be presented in a way that would enable patients to participate actively in the decision if that were their choice.
So how should clinicians address cholesterol in 2017 (Figure). Except for extreme phenotypes, the decision is about risk reduction, not cholesterol levels. The evidence-based lipid-lowering drugs seem to lower risk even if a patient’s initial LDL is low; they are risk-reduction medications. Two people may choose different strategies and both be right based on their preferences. The key is that clinicians do not dictate treatments but help inform choices. Different people may choose differently, and all be correct for what is important to them.
So first, orient the patient to ASCVD risks and determine risk based on prior ASCVD events, risk calculator, or coronary calcium score. Promote a healthful lifestyle for everyone, with attention to smoking cessation, healthful diet, regular physical activity, and optimal weight. Then, discuss benefits, risks, and costs of evidence-based lipid-lowering therapy, helping patients understand what they stand to gain and what it will take to get there. For people at highest risk, including those who have already experienced an ASCVD event, treatment with high-dosage, high-intensity statins (eg, atorvastatin 80 mg/d) can best reduce risk with minimal adverse effects and cost. For lower-risk individuals, treatment with statins provides a smaller benefit, but many will find the benefits to outweigh risks. In this case, it is prudent to begin with a lower dosage of statins (eg, atorvastatin 20 mg/d) and intensify depending on the patient’s preference for greater risk reduction. For those who have experienced an event and desire even more risk reduction, nonstatin treatment may be considered using ezetimibe first, and then, possibly, evolocumab. For those who have a mild or moderate intolerance to statins, another statin may be tried before progressing to the evidence-based nonstatin therapies. For those with a severe reaction, the use of evidence-based nonstatins would be preferred. In all cases, the use of medications without outcomes evidence should be avoided, especially those with safety concerns. Physicians can consider lipid-level testing as a tool to evaluate adherence, in partnership with patients. Finally, best practice should involve regular reassessment of the patient’s preference, medication approach, and tolerance to the medication.
The overarching goal is to derive maximum benefit from clinical care while maintaining alignment with each patient’s preferences and goals. The strongest treatment recommendations should be where the risk is highest, the evidence is robust, and the cost is affordable. The use of statins for higher-risk patients and the judicious use of other evidence-based options, partnership in decision making with patients, and wise reliance on healthful lifestyles provide the best hope of success in preventing the morbidity and mortality caused by cardiovascular disease.
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Article Information
Published Online: July 24, 2017. doi:10.1001/jama.2017.6753
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported that he received research grants from Medtronic, Johnson & Johnson (Janssen), the US Food and Drug Administration, all through Yale; works under contract with the Centers for Medicare & Medicaid Services; chairs a cardiac scientific advisory board for UnitedHealth; is a participant and participant representative of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science and the Physician Advisory Board for Aetna; and is the founder of Hugo, a personal health information platform.
Additional Contributions: The author thanks Suveen Angraal, MBBS, Maria Johnson, MBA, and Erica Spatz, MD, Yale School of Medicine; Marilyn Mann, JD; Khurram Nasir, MD, Baptist Health South Florida, Miami; and Karol Watson, MD, PhD, Department of Medicine/Cardiology, Barbra Streisand Women’s Heart Health Program, David Geffen School of Medicine at UCLA, for their thoughtful review of this work, for which they were not remunerated.
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