LDL-C and Non–HDL-C as Major Targets of Therapy
Most guidelines identify LDL as the primary atherogenic lipoprotein—and therefore the dominant target of cholesterol-lowering therapy.20,384 But growing evidence indicates that VLDL is similarly atherogenic.20,385 Many investigators thus contend that combining LDL-C and VLDL-C into non–HDL-C is preferable to LDL-C alone.386 Non–HDL-C can also be called atherogenic cholesterol. The major apolipoprotein of LDL and VLDL is apo B; for this reason, the measurement of total apo B is an alternative to non–HDL-C.56 The measurement of total apo B can be converted to the total lipoprotein particle number for apo B–containing lipoproteins; this conversion is possible because there is one apo B molecule per lipoprotein particle. According to several reports, total apo B (or lipoprotein particle number) is a better predictor of ASCVD than is LDL-C.320,387,388,389,390,391,392,393,394,395 A few reports claim that apo B is superior to non–HDL-C in prediction of ASCVD,55,396,397 but other investigators report that non–HDL-C is superior to apo B.53,398,399 Regardless, the difference in predictive power between the two is small.
Cholesterol-Lowering Therapy in Secondary Prevention
Many RCTs document that statin therapy reduces risk of recurrent cardiovascular events in patients with established ASCVD.20,322,400,401,402 Risk reduction occurs regardless of baseline LDL-C (or non–HDL-C) levels. Several RCTs report that risk reduction with statin therapy extends to LDL-C ranges of 70 to 80 mg/dL.403,404,405,406,407,408,409 Statin treatment reduces strokes as well as CHD, as shown in several RCTs and, particularly, in one trial designed to test effects on stroke.410 Based on RCT evidence, it is reasonable to maximize statin therapy in patients with established CHD.
A critical question is whether further cholesterol lowering beyond maximal statin therapy will give additional risk reduction. Recent American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines411 concluded that RCT evidence is insufficient to justify adding other nonstatin drugs to statin therapy. Nonetheless, it may be worthwhile to review their potential. Examples include bile acid resins, ezetimibe, nicotinic acid, fibrates (eg, fenofibrate), and n-3 fatty acids.
Until recently, the only agent systematically tested as an add-on drug was nicotinic acid. As mentioned, adding nicotinic acid to statin therapy failed to achieve additional risk reduction for ASCVD.348,349 This was true even though previous studies showed that adding nicotinic acid to statins favorably reduced carotid atherosclerosis in imaging studies.347 Even so, in the light of large outcome trials, nicotinic acid cannot be considered a first-line, add-on drug in secondary prevention.
Fenofibate, a fibrate, resembles nicotinic acid in that it lowers VLDL and LDL and raises HDL-C.412 Among fibrates, fenofibrate is preferred over gemfibrozil when used with statins because it is accompanied by a lower risk of severe myopathy.413 Nonetheless, in one recent study in patients with diabetes, the combination of statin plus fenofibrate failed to reduce ASCVD risk more than statin alone.414 Still, in meta-analysis of results in hypertriglyceridemic patients from this study, combination therapy showed a strong trend toward greater benefit compared to statin alone.415 This result accords with subgroup meta-analysis of hypertriglyceridemic in all fibrate trials; together, they showed greater risk reduction were used compared to placebo.341 A similar favorable trend from fibrate therapy was not found in subgroups without hypertriglyceridemia. In sum, meta-analysis supports the concept that adding fenofibrate to statin therapy is an option for high-risk patients with hypertriglyceridemia.
Many providers add n-3 fatty acids to statin therapy on the belief that additional risk reduction will be achieved. In two secondary prevention trials, adding n-3 fatty acids to statin treatment, however, did not produce additional benefit.416,417 But in contrast, in the JELIS [Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study] trial,298 adding eicosapentaenoic acid to statins in patients with ASCVD caused a reduction in cardiovascular events. Thus, the benefit of adding n-3 fatty acids to statin therapy remains open to question. Some investigators prefer n-3 fatty acids in combination with statins to treat hypertriglyceridemia because they do not raise the risk of severe myopathy.
Another potential add-on drug is ezetimibe. This agent was combined with a statin in the IMPROVE-IT trial.159 The combination of maximal simvastatin therapy plus ezetimibe significantly reduced recurrent ASCVD events in patients who had recent acute coronary syndromes compared with simvastatin alone. The addition of ezetimibe reduced LDL-C levels to well below 70 mg/dL, which was the approximate level attained by simvastatin alone. This study makes several important points. First, it undercuts any notion that statins are the only cholesterol-lowering drug that can reduce ASCVD events. Second, it supports the concept of “the lower, the better” for atherogenic cholesterol in patients with established ASCVD. Third, it reinforces the cholesterol hypothesis by showing that a drug that uniquely lowers cholesterol levels will decrease risk.
Hot on the heels of the IMPROVE-IT trial was approval of PCSK9 inhibitors by US and European regulatory agencies. Monoclonal antibodies against PCSK9 free up LDLRs and dramatically reduce serum LDL-C levels.418 Recent reports333,334 further document a striking reduction in LDL-C when PCSK9 inhibitors are combined with statins in high-risk patients. They further showed preliminary data in which this combination enhanced reduction of CHD and stroke.
Cholesterol Goals in Secondary Prevention
There are two ways to approach the question of cholesterol goals in secondary prevention. First, the meta-analysis of the Cholesterol Treatment Trialists’ (CTT) Collaboration322 showed that for every mmol/L lowering of LDL-C there was an approximate 22% reduction in relative risk of ASCVD events (see Fig. 29–11). On average, for every 1% reduction in LDL-C, risk is reduced by 1%. This means that a 50% reduction in LDL-C should reduce risk by 50%. For simplicity, this meta-analysis supported the concept of “the more, the better” for LDL-C reduction. The 2014 ACC/AHA guidelines implicitly accepted this conclusion when it recommended high-intensity statins in patients with ASCVD. For example, treatment with either atorvastatin 80 mg/day or rosuvastatin 20 mg/day should achieve a “more-the-better” goal of 50% reduction of LDL-C. Based on the IMPROVE-IT trial, an even greater reduction of LDL-C (eg, ≥ 60%), attained by adding ezetimibe to a high-intensity statin, could be recommended by the same rationale.
An alternate approach to a cholesterol goal can be based on a meta-analysis of statin trials that examines maximal risk reduction that can be achieved by cholesterol lowering.419 The results of this analysis showed “the lower, the better” for cholesterol lowering. That is, the lowest levels of LDL-C (or non–HDL-C) were accompanied by the lowest risk of future ASCVD events. This relationship held to an LDL-C of less than 50 mg/dL. Similar results were obtained for non–HDL-C. This “lower-is-better” relationship is supported by the IMPROVE-IT trial. At the least, an LDL-C goal for secondary prevention can be reasonably set at less than 70 mg/dL, but based on IMPROVE-IT, a case can made for a still lower goal. In the future, RCTs with PCSK9 inhibitors may call for a very low goal for atherogenic cholesterol levels.
Cholesterol-Lowering Therapy for Primary Prevention
Optimal Cholesterol Levels in Primary Prevention
There is no simple answer to the question of what is the optimal LDL-C (or non–HDL-C) for primary prevention. Several epidemiological studies indicate that CHD risk is progressively lower as total cholesterol reduces to 150 mg/dL.420,421 This level corresponds to an LDL-C of about 100 mg/dL.20 Genetic epidemiology further demonstrates that lifetime levels of LDL-C of approximately 100 mg/dL are accompanied by a low lifetime risk of CHD.153,422,423 Moreover, RCTs with cholesterol-lowering drugs show that reducing LDL-C concentrations to near 100 mg/dL or below produce significant reduction in ASCVD rates.20,424 Based on these congruent lines of evidence, the Adult Treatment Panel (ATP) III20 defined an LDL-C level of less than 100 mg/dL as being optimal, whereas 100 to 129 mg/dL was called near optimal. On the other hand, this so-called optimal level may not be the most efficacious level for high-risk patients, who may benefit from still further cholesterol lowering.
Selection of Patients for Drug Therapy in Primary Prevention
Three methods have been used for selection of patients for initiation of cholesterol-lowering drugs. These are (1) 10-year risk for ASCVD based on multiple-risk-factor algorithms (global risk assessment), (2) lifetime risk based on single major risk factors, and (3) 10-year risk based on imaging for subclinical atherosclerosis. Each approach can be briefly reviewed for its strengths and weaknesses.
Ten-Year Risk Estimates Based on Multiple-Risk-Factor Algorithms
These algorithms have been developed from various test cohorts. The most widely used in the United States is that derived from a population in Massachusetts, the Framingham Heart Study.425 The Framingham cohort included several thousand subjects studied over many years. Recently, the National Heart, Lung and Blood Institute commissioned the creation of a new algorithm based on five cohorts, including Framingham. This algorithm is currently sponsored by the AHA and the ACC. It was published in 2013 and will be called the 2013 ACC/AHA risk algorithm.426 It can be accessed online (http://tools.acc.org/ASCVD-Risk-Estimator/).
Similarly, QRISK is an ASCVD risk assessment tool developed in the United Kingdom that derives from a large prospective, open-cohort study.427 The derivation cohort for this algorithm included 1.28 million individuals (aged 35-74 years and free of diabetes and ASCVD). The validation study contained 610,000 subjects from 160 practices. A comparison study indicated that the Framingham study overpredicts risk compared to QRISK by about 35%.427 This algorithm is available online (http://qrisk.org/). A major strength of QRISK lies in its much larger size compared to US algorithms.
In essence, multiple–risk factor algorithms use population averages to predict risk in individual patients. When applied in guidelines, they assume that individuals resemble population means. A major limitation of this approach is that risk in individuals can vary substantially from the population mean. This is particularly so in older persons who exhibit wide variability in atherosclerotic burden. Moreover, population risk tends to decline over time, as suggested by QRISK versus Framingham.427 Consequently, population-risk algorithms derived in the past tend to overestimate current risk. This is illustrated by recent reports showing that application of the ACC/AHA algorithm overestimates population risk when tested in more recently studied cohorts.428,429,430,431,432,433 A risk algorithm developed in one country does not necessarily hold in another; for example, various studies have shown that Framingham algorithms overestimate CHD risk in several countries.434
Lifetime Risk Assessment Based on Algorithms and on Individual High-Risk Conditions
If lifetime risk estimates were to be reliable, they would have utility for deciding on treatment strategies. Online estimates for lifetime risk are provided by both 2013 ACC/AHA (http://tools.acc.org/ASCVD-Risk-Estimator/) and QRISK (http://www.qrisk.org/lifetime/). These are not as reliable as 10-year risk estimates because long-term risk is not as well substantiated. An alternate and simpler approach is to identify higher risk conditions and to use these as a guide to lifetime risk reduction (Table 29–9).
TABLE 29–9.High-Risk Conditions ||Download (.pdf) TABLE 29–9. High-Risk Conditions
Chronic kidney diseasec
Heavy cigarette smokingd
Any of these conditions carry a relatively high lifetime risk, as can be shown by risk algorithms. The presence of higher risk conditions makes 10-year risk assessment unnecessary. Most such patients deserve serious consideration of statin treatment. Use of this strategy will shift drug administration to an earlier age than will current 10-year risk algorithms. Practical considerations make RCTs testing lifetime therapies unrealistic. But RCTs have been carried out in persons with each high-risk condition, and they show efficacy for shorter term risk.435,436 RCTs demonstrating efficacy of cholesterol-lowering therapy have been documented in patients with diabetes,437 metabolic syndrome,438,439,440 CKD,327 cigarette smoking,441 hypertension,442 and hypercholesterolemia.443 Therefore, lifetime risk reduction is almost certain when used in patients with higher risk conditions.
Ten-Year Risk Assessment Based on Atherosclerosis Imaging
A major drawback of global risk algorithms is that they place excessive weight on age as a risk factor. In essence, age is used as a surrogate for progressive atherosclerosis. The impact of age on estimated risk is so powerful that most men over 60 years and most women over 70 years are recommended for statin therapy.411 Atherosclerotic burden increases with age in the population as a whole; yet many older individuals have little or no atherosclerosis. They will not benefit from taking statins. One way to improve identification of individuals without atherosclerotic burden is to measure subclinical atherosclerosis. The most readily available and intensively studied modality for atherosclerosis imaging is coronary artery calcium (CAC).444,445 Measurement of CAC in older individuals who are at relatively low risk by global risk assessment will uncover a substantial portion who are devoid of coronary atherosclerosis.446,447 Recent studies show that actual 10-year risk for clinical CHD when CAC is zero is very low (see Table 29–9).448 In the absence of CAC, statin treatment is not needed.449
Atherosclerosis imaging may be particularly useful under the following circumstances: absence of high-risk conditions (Table 29–10), estimated 10-year risk for ASCVD in the range of 5% to 19% by global risk assessment,426 presence of emerging risk factors in otherwise lower risk individuals (see Table 29–10), and statin intolerance in persons without ASCVD. As shown in Table 29–10, individuals with a zero CAC Agatston units are virtually free of CHD after 10 years.448 These individuals will not need statin therapy. If CAC scores are in the range of 1 to 99 Agatston units, risk is borderline, and statins are optional. The decision should be made on a variety of factors previously considered. At higher CAC scores (> 100 Agatston units), use of statins is reasonable.
TABLE 29–10.Predicted 10-Year Risk for Coronary Heart Disease (CHD) According to Age and Coronary Artery Calcium (CAC) ||Download (.pdf) TABLE 29–10. Predicted 10-Year Risk for Coronary Heart Disease (CHD) According to Age and Coronary Artery Calcium (CAC)
10-year Risk for CHD
10-year Risk for CHD
(> 75 years)
|Zero ||1% ||1% |
|1–99 ||4% ||7% |
|≥ 100 ||17% ||18% |
Risk Classification for Primary Prevention
The following are classifies risk categories that can be applied to primary prevention.
High risk. ATP III guidelines categorized patients according to absolute risk. These guidelines pointed out that patients with established ASCVD have a 10-year risk of recurrent events exceeding 20%. Patients who exceeded this risk but had no history of ASCVD were said to have CHD risk equivalents. This nomenclature is no longer used, but identifying those at high risk, whose risk is as high as ASCVD patients and who deserve more intensive cholesterol-lowering therapy, may still be useful.
Moderately high risk. There is no agreement at present on what constitutes moderately high risk. At this level, risk is high enough to justify cholesterol-lowering drugs, but it is less than that of patients with ASCVD. The ACC/AHA guidelines set a 10-year risk for statin consideration of 7.5% or more. The National Institute of Health and Care Excellence (NICE) guidelines recommend a threshold of ≥ 10%. In neither of the recent guidelines was an upper boundary set, and moderately high risk and high risk were not distinguished. In this document, moderately high risk will be defined as a 10-year risk of ASCVD of 7.5% to 19% and thus will be distinguished from high risk. This distinction may be useful in selection of intensity of statin therapy.
Higher lifetime risk. At the next lower level, some patients can be said to be at relatively low 10-year risk but a higher lifetime risk (ie, 35%-50%). One way to identify these patients is through a multiple risk factor algorithm—available from the ACC/AHA (http://tools.acc.org/ASCVD-Risk-Estimator/) or QRISK (http://www.qrisk.org/lifetime/). Another way to identify a high lifetime risk in current lower risk individuals is through the presence of higher risk conditions (see Table 29–10). Among these are persistently high LDL-C levels (≥ 160 mg/dL), and especially those with very high LDL-C (≥ 190 mg/dL).
Cholesterol Goals in Primary Prevention
There are two reasons to establish goals for atherogenic cholesterol in primary prevention. The first is to prevent ASCVD events in the short-term (eg, 10 years) and the second is the need to prevent events over a lifetime. Table 29–11 poses a strategy to achieve these aims.
TABLE 29–11.Number Needed to Treat with Cholesterol-Lowering Drugs to Prevent One ASCVD Event over 10 Years ||Download (.pdf) TABLE 29–11. Number Needed to Treat with Cholesterol-Lowering Drugs to Prevent One ASCVD Event over 10 Years
Risk for ASCVD
|Number Needed to Treat |
|5% ||50 |
|7.5% ||33 |
|10% ||25 |
|12.5% ||20 |
|15% ||17 |
|17.5% ||14 |
|20% ||12 |
|22.5% ||11 |
|25% ||10 |
For high-risk individuals, whose 10-year risk is equivalent to that of a patient with established ASCVD (ie, ≥ 20%), cholesterol lowering should be as intense as in ASCVD patients. Accordingly, the goal can be either a 50% reduction in LDL-C levels, or alternatively, a target non–HDL-C of less than 100 mg/dL (LDL-C < 70 mg/dL). For most patients, a high-intensity statin can be justified. If the goals of therapy are not achieved, a nonstatin add-on agent can be considered. If only a moderate-intensity statin can be tolerated, consideration can be given to adding ezetimibe or bile acid resin.
For those at moderately high risk (ie, 10-year risk in the range of 7.5%-19%), the use of a high-intensity statin, as recommended by ACC/AHA guidelines, or a moderate-intensity statin, as proposed by NICE, is an option. At this risk level, atherogenic cholesterol should be reduced by at least 40%, or alternatively, to an LDL-C goal of less than 100 mg/dL (or a non–HDL-C goal of < 130 mg/dL).
For lower risk individuals whose lifetime risk is high (eg, 35%-50%), the LDL-C likewise should be reduced to less than 100 mg/dL. The same goal should be set for patients with was very high LDL-C. In both cases, the aim is to slow progression of atherosclerosis so as to reduce lifetime risk.
The decision to initiate a lifetime of statin therapy should not be taken lightly. For therapy to be successful, the patient becomes a key partner in the treatment regimen. Before starting a statin, several issues should be discussed or considered as options. These can be reviewed briefly.
Discontinuation of prescribed statin is a common issue in clinical practice. It has been shown that failure to sustain statin therapy results in higher rates of ASCVD after MI. Poor adherence to statins can be attributed to many factors, among which are health system factors, provider behavior, and patient behavior.450 The first step in overcoming failure to adhere is to review strategies for maintaining compliance in patient discussion.
Consideration of Drug Side Effects
Most patients tolerate statins and other cholesterol-lowering drugs without significant side effects. As already mentioned, some patients complain of a variety of side effects of statins: statin-associated adverse muscle events, hyperglycemia, cognitive dysfunction, and neuropathy. Statins also can increase plasma glucose, which may cross the threshold for categorical diabetes. This may be alarming, but is not a serious side effect. Unfortunately, many patients have a preconceived anticipation of drug side effects and often blame various symptoms on their drug. If complaints arise, physicians should thoroughly discuss symptoms and make an effort to separate real from imagined statin intolerance. By encouragement, it is often possible to successfully restart and maintain statin therapy. For those who cannot tolerate statins, a variety of strategies, as discussed before, can be used to achieve a satisfactory cholesterol lowering.
Alternatives to Statin or Add-on Drugs
Statins are first-line cholesterol-lowering therapy, but if they are not tolerated, other ways to achieve cholesterol goals can be considered. Efforts should be doubled to start and maintain lifestyle modification, which can lower cholesterol levels by 10% to 15%.20 Both bile acid resins and ezetimibe can lower LDL-C by 15% to 25%. Ezetimibe plus a moderate-intensity statin will reduce cholesterol levels as much as high-intensity statins. Fibrates and niacin are alternative add-on drugs for patients with hypertriglyceridemia. Finally, in patients with severe hypercholesterolemia, PCSK9 inhibitors may be an option for patients who are statin intolerant, especially in those with ASCVD or very high LDL-C levels.
With introduction of generic statins, drug costs have declined greatly. For some patients, however, overall cost of therapy is a significant issue. Expenses mount with regular monitoring for response, clinical management of side effects, and time and expense of travel to provider locations. In patients who are at borderline risk, these factors deserve consideration as to whether to institute statin therapy.
Some physicians find the number need to treat (NNT) to be useful in discussions with patients. NNT is the number of people needed to treat to prevent one ASCVD event over a given period of time. Periods of time may be 5 years (the duration of most RCTs), 10 years (the usual absolute risk projection), or a lifetime. Table 29–11 illustrates the NNT for statin therapy at different 10-year risk estimates for moderate-intensity and high-intensity statins.
The NNT for a lifetime of therapy will be much lower, depending the age at which statin therapy is started. A low lifetime NNT constitutes the strongest rationale for a lifetime of statin therapy in primary prevention.
Most patients who have persistent major risk factors deserve consideration for statins (see Table 29–11); they have a relatively high lifetime risk. In addition, some investigators use emerging risk factors in risk assessment (Table 29–12).451
TABLE 29–12.Emerging Cardiovascular Risk Factors ||Download (.pdf) TABLE 29–12. Emerging Cardiovascular Risk Factors
Lipid markers (triglycerides, HDL-C, Lp(a), apolipoprotein, particle size)
Inflammatory markers (C-reactive protein, fibrinogen, interleukin-6, leukocyte count)
Prothrombotic markers (fibrinogen, PAI-1, von Willebrand factor, D-dimer)
Dysglycemic markers (prediabetes, hemoglobin A1c, insulin)
Renal markers (creatinine, uric acid)
Family history of premature ASCVD
The most commonly used factor is C-reactive protein.424 Others include low HDL-C, hypertriglyceridemia, family history of premature ASCVD, elevated fibrinogen, prediabetes, and elevations of Lp(a). Although measurements of any or all of these emerging risk factors are not routinely recommended by guideline committees, they are an option for patients whose indications for statins are borderline.
Current cholesterol guidelines place high emphasis on use of statins in older persons. This is because risk assessment algorithms give heavy weight to age as a risk factor. Unfortunately, these algorithms become less reliable with advancing age.452 This places a greater responsibility on clinicians who care for older persons. One solution to this dilemma is to measure subclinical atherosclerosis. For example, older individuals who are free of CAC have a very low risk for future ASCVD events. On the other hand, if CAC levels are high, the clinician is justified in advocating statin therapy. In addition, if an older person has long-standing, major risk factors, statin therapy is warranted. There is little doubt that high-risk, older persons will benefit from statins treatment; this is been adequately demonstrated in RCTs.453,454
The benefit of statin therapy for women having ASCVD is well documented.154 Their utility for primary prevention has been questioned455,456,457,458 (http://tinyurl.com/7ywndqe). At comparable ages, women generally have lower absolute risk than men. Therefore, close attention should be given to absolute risk estimates when contemplating statin usage and women. Some of the factors that favor statin therapy include diabetes, heavy cigarette smoking, multiple risk factors (eg, metabolic syndrome), hypercholesterolemia, and a strong family history of premature ASCVD.