A perspective on cholesterol management

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.

JAMA Network

 


JAMA Network

Viewpoint

August 2017

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 Adults 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,

7 hemorrhagic strokes,

while averting about 1000 events among those with preexisting disease,

and 500 among those with elevated risk but without preexisting disease. 

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.

More evidence-based options have emerged for secondary prevention. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) reported that adding ezetimibe to effective statin therapy in stable patients who experienced an acute coronary syndrome reduced LDL-C from 70 to 54 mg/dL, 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) trial reported that adding evolocumab, a PCSK9 inhibitor, to effective statin therapy reduced LDL-C from 92 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 FDA 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) trial 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.

So how should clinicians address cholesterol in 2017. 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.