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The role of lipid-lowering therapies: A look at the guidelines
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Significant controversy accompanied the release of the American College of Cardiology and American Heart Association cholesterol guidelines in late 2013. One of the most controversial points was the elimination of LDL cholesterol and non-HDL cholesterol goals, which were central to the National Cholesterol Education Program Adult Treatment Panel III guidelines and were used for more than a decade in clinical practice. The rationale for elimination of these goals was a paucity of evidence to support this approach as most clinical trial data did not target specific LDL or non-HDL goals.
The ACC/AHA guidelines focus on four statin benefit groups. This is because fixed-dose statins were used in most clinical trials with CV outcome data. This has led to the belief that percent LDL reduction is more important than achieving target numbers. As one can expect, there is clinical controversy regarding this new approach, although high-intensity statins can decrease LDL levels by approximately 50% from baseline. With the introduction of these guidelines, the annual monetary generation from statins may increase to nearly $20 billion. The combination of sales from prescription niacin, fenofibrate and ezetimibe (Zetia, Merck) is currently about $5 billion per year, which would likely decline.
In September, the National Lipid Association (NLA) put forth its own lipid guidelines. Of note, this is only the executive summary of part one. Although it also included a slide set, it is unknown when the complete version or part two will be released. The NLA guidelines reintroduced LDL goals and placed more emphasis on non-HDL, which in observational studies was more predictive of atherosclerotic CVD (ASCVD) compared with LDL. Similar to the ACC/AHA guidelines, the NLA advocates moderate- or high-intensity statins as first-line therapy. However, if a high-intensity statin does not achieve targeted goals, the addition of other lipid-lowering agents is recommended.
Alexander Kantorovich
Diana Isaacs
A meta-analysis published in 2014 demonstrated that LDL levels < 50 mg/dL were associated with significantly lower risk for major CV events compared with LDL levels of 50 mg/dL to < 75 mg/dL and 75 mg/dL to < 100 mg/dL. Also, the IMPROVE-IT trial presented at the AHA Scientific Sessions in November found that lower LDL levels achieved through addition of ezetimibe to simvastatin reduced major CV outcomes after ACS compared with simvastatin alone, although both groups achieved median follow-up LDL levels < 70 mg/dL (53.7 mg/dL vs. 69.5 mg/dL in the ezetimibe/simvastatin and simvastatin groups, respectively). IMPROVE-IT was the first trial in which adding an adjunct lipid-lowering agent to a statin produced clinical benefit.
This has led clinicians to question when it is appropriate to utilize adjunct lipid-lowering medications. The NLA does not specify which agent to add, except preference is given to fibrates, niacin or omega-3 fatty acids when triglycerides are > 500 mg/dL. The ACC/AHA states that adjunct agents could be considered in high-risk individuals who cannot tolerate high-intensity statins or do not achieve the expected percent reduction from high-intensity statins. However, the ACC/AHA recommend first reinforcing adherence to lifestyle and statin therapy.
Role of niacin for dyslipidemia
Niacin, also known as nicotinic acid or vitamin B3, lowers LDL by up to 25%, triglycerides 50%, non-HDL 23%, raises HDL up to 35% and reduces lipoprotein(a). Of all the agents used for dyslipidemia, niacin is the most effective for raising HDL and is second only to statins for the reduction of LDL and non-HDL. However, raising HDL in individuals who have already achieved goal LDL levels has not demonstrated improved outcomes in clinical trials.
Niacin has been studied extensively in large dyslipidemia trials such as the Coronary Drug Project, the FATS trial, the ARBITER trials, AIM-HIGH and HPS-2 THRIVE. Although niacin and most other adjunct antihyperlipidemic agents have failed to make a difference in clinical outcomes when optimal LDL levels were already achieved with statins (AIM-HIGH, HPS-2 THRIVE), other studies have reported a reduction in CV events with niacin, although significant mortality differences were not observed (Coronary Drug Project). There have been no clinical trials to date in which a combination of niacin with a statin reduced major CV events, although surrogate endpoints such as carotid intima–media thickness, atherosclerotic plaque regression and coronary stenosis regression were positively affected.
Extended-release tablets (Niaspan, AbbVie) have reduced the bothersome adverse effect of flushing, but other safety concerns include increased rates of diabetes, bleeding complications and myopathies. The ACC/AHA comment that the use of niacin or fenofibrate may require down-titration of statin intensity to improve safety, which may result in suboptimal use of evidence-based high-dose statin therapy.
Role of fibrates
Fibrates include gemfibrozil and fenofibrate, and they are generally reserved for triglycerides > 500 mg/dL to reduce the risk for pancreatitis. They lower non-HDL up to 19%, raise HDL up to 20%, lower triglycerides up to 50% and have a minor impact on LDL. The ACC/AHA guideline recommends against use of gemfibrozil with statins due to an increased risk for muscle symptoms and rhabdomyolysis. Fenofibrate can be considered with a low- or moderate-intensity statin in high-risk patients. The NLA guidelines list fibrates as an option if non-HDL is not achieved with high-intensity statin alone or if triglycerides are > 500 mg/dL.
Ezetimibe comeback
The NLA recommendation states that ezetimibe is a safe, evidence-based non-statin therapy that may be used after ACS as well as in other patients who do not achieve therapeutic targets. The recent IMPROVE-IT trial demonstrated that ezetimibe had improved CV outcomes when added to simvastatin in patients after ACS, whereas trials with niacin in combination with statins have not demonstrated these effects. Ezetimibe lowers LDL by up to 20%, non-HDL up to 19%, triglycerides up to 11% and raises HDL up to 5%. No significant differences in adverse effects including cancer, muscle- and gallbladder-related events or transaminitis were observed in IMPROVE-IT.
With a substantially cleaner safety profile than niacin or fibrates, ezetimibe may now be the agent of choice in patients intolerant to statins or who need additional LDL or non-HDL reduction.
Clinician choices
Each clinician will have to decide which guidelines to follow in clinical practice.
Although statins are first-line agents in both guidelines, other lipid-lowering medications continue to have niches in lipid management, especially in patients intolerant to statins. Fibrates and omega-3 fatty acids are utilized mostly in patients with significant hypertriglyceridemia (triglycerides > 500 mg/dL) at risk for pancreatitis. Niacin may be best utilized in patients with elevated lipoprotein(a) concentrations, and possibly those in whom additional LDL or triglyceride lowering is desired, although it lacks CV outcome data when added to statins and should not be used solely to raise HDL levels.
Ezetimibe may be the biggest winner of all the adjunct lipid-lowering medications. Unlike fibrates and niacin, there is not an increased risk for myopathy and liver toxicity when combined with statins. With the NLA guidelines reintroducing LDL and non-HDL goals, the positive outcomes from the IMPROVE-IT trial and the drug coming off patent in late 2016, it seems like all the ducks are in a row for ezetimibe to make a big comeback in lipid management as an adjunct to statin therapy.
For more information:
Alexander Kantorovich, PharmD, BCPS, is clinical assistant professor in the department of pharmacy practice at Chicago State University College of Pharmacy and clinical pharmacy coordinator, internal medicine, in the pharmacy department at Advocate Christ Medical Center, Oak Lawn, Ill. Diana Isaacs, PharmD, BCPS, BC-ADM, is clinical assistant professor at Chicago State University College of Pharmacy. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at University of the Sciences in Philadelphia. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.
Disclosure: The authors report no relevant financial disclosures.
Perspective
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Roger S. Blumenthal, MD
There have been strong trends for benefit in fibrate trials when the baseline triglycerides are > 200 mg/dL and the HDL-C is low. Even in AIM-HIGH, there was a strong trend for benefit in those subjects with an HDL-C < 33 mg/dL and a triglyceride > 200 mg/dL. A VA system study is starting that is looking at add fenofibrate to a high potency statin vs. statin alone in subjects with a triglyceride level of > 200 mg/dL. It will be interesting to see if the IMPROVE-IT results lead many clinicians to target an LDL-C of < 55 mg/dL in high risk secondary prevention patients. Regardless, most clinicians now feel reassured that ezetimibe’s mechanism of action is safe and well-tolerated and will feel much more comfortable of using ezetimibe in patients who cannot tolerate a moderate dose of a high potency statin in both the primary and secondary prevention settings.
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