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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 cardiovascular 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 Zetia (ezetimibe, 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.
A meta-analysis published in 2014 demonstrated that LDL levels less than 50 mg/dL were associated with significantly lower risk for major CV events compared with LDL levels of 50 mg/dL to less than 75 mg/dL and 75 mg/dL to less than 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 acute coronary syndromes (ACS) compared with simvastatin alone, although both groups achieved median follow-up LDL levels less than 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 greater than 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 levels. 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.
Niaspan (extended-release niacin tablets, 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 may require down-titration of statin intensity to improve safety, which may result in suboptimal use of evidence-based statin therapy.
Role of fibrates
Fibrates include gemfibrozil and fenofibrate, and they are generally reserved for triglycerides greater than 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 cholesterol. 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 greater than 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 most 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.
Disclosure:
- The authors report no relevant financial disclosures.
Perspective
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Yehuda Handelsman, MD, FACP, FACE, FNLA
The ACC/AHA cholesterol guidelines do not really address direct and clinically relevant individual patient care. The authors considered population values based merely on the average response in clinical trials. Thus, within a study population, up to 50% of the patients would have a lesser response to a statin, making the concept of moderate potency or high potency statin not practical for many patients. Although many of the studies were designed based on the dose of a specific statin and did not specify LDL targets, the results universally pointed to a better outcome based on the LDL level achieved. Thus, the authors’ removal of LDL goals from the guidelines, with a mere recommendation for generic use of statins, represents a skewed translation of study averages to clinical practice.
To me, the ACC/AHA guidelines are not for clinicians. Perhaps these guidelines, by simplifying lipid management to merely prescribing a statin, are good for people who would rather not manage lipids and, thus, would not need to know how. To the practicing physician, to make a treatment decision based on population status and not on patient characteristics is wrong. I think more than that, the database they used was so restricted that it really did not represent the majority of patients — clearly it did not represent the patients with diabetes who I manage.
The authors chose to rely only on grade A data; however, many of these studies did not cover a large majority of our patients. The authors should have incorporated a grade B or grade C studies and expert opinion that cover varied subgroups rather than taking narrow population-based studies and applying them universally. In short, applying results that cover population A to population D, which was not part of the study, simply because population D does not have a grade A study is wrong. The guideline authors applied results across uncovered populations and also left many groups with no recommendations at all. We do not need a technical analysis of results; we need clinically relevant guidelines to help us manage all our patients.
The American Association of Clinical Endocrinology retained lipid targets in its just-published 2015 diabetes guidelines, of which I am an author. We did not find any new studies or relevant data to justify changes to clinical practice. In fact, the recent IMRPOVE-IT trial showed that adding ezetimibe on top of a statin did bring further improvement in outcomes. Some would maintain that ezetimibe on top of simvastatin contributed only a relative risk reduction of 10% and an absolute risk reduction of 2%, yet the majority of the statin trials showed an absolute risk reduction ranging from 2.5% to 4.5% — which is not that much more.
Clinical endocrinologists as well as clinical cardiologists who deal with direct patient care are well-versed in lipids and their management to reduce atherosclerosis. Our patients with diabetes have not only LDL issues, but present with high non-HDL, which means changes in triglycerides and in HDL. The lack of studies should not disregard the experts’ ability to reduce risk in high-risk patients and to use combination medications as needed.
In the statin trials, efficacy was generally 15% to 45%; although statins reduced risk significantly, they did not eliminate the majority of the disease burden. So, experts are focusing on the residual risk. A comprehensive-approach person like me also looks beyond lipids — at blood pressure, glucose, anticoagulation — and addresses those issues as well. However, I would maintain that because of the persistent residual risk, we ought not just control the triglyceride and HDL components, but address further reduction of LDL. In the majority of the studies, LDL levels stayed in the 70s and 80s. Hence, it may be that residual risk is not just low HDL or high trigylcerides, but that LDL did not reach low enough targets.
Although the ACC/AHA guidelines mention an occasional need for lipid management with combination therapy, this was largely lost in view of the headlines highlighting no therapy beyond statins and no need to monitor with lipid panels. Unfortunately, many insurance companies took the cue and are refusing to pay for lipid panels beyond the initial test or for an additional medication on top of a statin, when necessary. I call on the authors to update their guidelines, add expert opinion and help us reverse the bad consequences of their recommendations for patients, especially those with high-risk and established CVD.
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