PRACTICE RECOMMENDATIONS
› Avoid adding niacin to statin therapy, as it does not appear to provide any added benefit and may increase the risk of stroke. B
› Continue statin therapy in a patient who has chronic kidney disease progressing to end-stage renal disease, but do not initiate it in patients on dialysis. B
› Do not add statins to the medication regimen of patients with heart failure; focus on optimizing therapies known to reduce mortality in this patient population instead. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Morbidity and mortality from atherosclerotic disease have decreased significantly in the last several decades, in large part because of advances in therapies targeting serum lipids—including statins.1 Since their introduction in 1987, HMG Coenzyme A inhibitors have been intensively studied, and their use has increased dramatically. A recent report from the National Center for Health Statistics reveals that in the years 1999 to 2002, 26% of men ages 65 to 74 years were taking statins; several years later (2005-2008), that number had soared to 50%. In the same time frame, statin use among women ages 65 to 74 went from 24% to 36%.2
Statins lower serum low-density lipoprotein cholesterol (LDL-C) and triglycerides, raise high-density lipoprotein cholesterol (HDL-C), and improve surrogate markers for cardiovascular events. Most importantly, statins reduce the risk for major cardiovascular events, such as myocardial infarction (MI) and death from cardiovascular disease (CVD), in select populations. Yet doubts about the benefits of statins, alone or in combination with other lipid-lowering agents, for certain patient populations remain.
Primary care physicians need to know when, or whether, to add a second lipid-lowering agent to the drug regimen of patients whose response to a statin is less than hoped for, and which patient populations and clinical indicators statins have not been found to help. You’ll find answers, the results of the latest studies, and details of the 2013 cholesterol guideline released last month by the American Heart Association/American College of Cardiology and in this evidence-based update.
A statin is not enough? Don't add these drugs
In patients with very elevated LDL-C or mixed dyslipidemias that fail to reach the desired lipid levels on statin monotherapy, other classes of lipid-modifying agents are often added in an attempt to improve clinical outcomes.3 Fibrates, extended release (niacin, and n-3 polyunsaturated fatty acids have been frequently used for this purpose. But it is only in the last several years that large, well-designed studies have looked closely at patient-oriented outcomes associated with statins in combination with other lipid-modifying drugs.4-9
Fenofibrate + a statin yields little benefit
The ACCORD lipid placebo-controlled trial studied fenofibrate as a simvastatin add-on in patients with diabetes.4 Its findings? While the lipid levels of patients receiving this drug combination improved significantly, the primary endpoint (MI, stroke, or death from cardiovascular causes) was no different from that of the controls, who were taking the statin alone.
Sub-group analysis suggested that the simvastatin-fenofibrate combination benefitted only one particular group: patients with high triglyceride levels (≥204 mg/dL) and low HDL-C (≤34 mg/dL). This finding prompted the US Food and Drug Administration to call for an additional clinical trial to evaluate the effectiveness of add-on therapy with fenofibrate in patients who meet this criteria.10 The status of such a study is uncertain.
Adding niacin to a statin does more harm than good
The HATS trial, published in 2001, found the addition of niacin to a statin regimen to be beneficial.7 But because of the wide confidence interval associated with the clinical endpoints and the small number of subjects (N=160) in that study, larger trials were needed to confirm the positive results. In fact, they found the opposite.
Niacin increases stroke risk. In both the AIM-HIGH5 (N=3414) and HPS2-THRIVE6 (N=25,673) trials, the addition of extended release niacin not only failed to reduce the risk of major cardiovascular events, it was shown to increase the risk of stroke.
n-3 polyunsaturated fatty acids don’t help much
Studies evaluating the addition of n-3 polyunsaturated fatty acids to statin therapy have had mixed results. The JELIS8 trial had more than 18,000 participants, 20% of whom had known coronary artery disease. All were taking statins and randomized to either open-label eicosapentaenoic acid (EPA) 600 mg 3 times daily or placebo. The primary endpoint, a composite of sudden cardiac death, fatal or nonfatal MI, unstable angina, angioplasty, and stenting or coronary artery bypass grafting, was lower in the intervention group: (2.8% vs 3.5%; number needed to treat [NNT]: 143).