Lipid biology and role in atherosclerosis
Cholesterol is a waxy compound manufactured by the intestines and the liver, is an essential component of cell membranes of mammals, and is present in nearly all animal products consumed (eggs, meat, milk, and so forth). HMG CoA reductase inhibitors (“statins”) block the rate-limiting step of endogenous cholesterol production. Cholesterol is not water soluble and needs lipoproteins for transport to different tissues. Lipoproteins are traditionally identified by their relative density and (in ascending order) are noted to be chylomicrons, VLDL (very-low-density lipoprotein), IDL (intermediate-density lipoprotein), LDL, and HDL. Of these, LDL is the most prevalent and the most scrutinized for its role in atherosclerosis. However, other non-HDL lipoprotein particles also contribute to atherosclerosis risk, particularly among patients with high triglycerides. Indeed, LDL levels in such patients may be misleadingly low. Triglycerides are the primary components of dietary fats, transported in chylomicrons and VLDL, and are closely associated with abnormal glucose metabolism. As concentrations increase, triglycerides are degraded to lipoproteins of various densities containing cholesterol and have been weakly linked to cardiovascular disease.
Cholesterol-rich LDL and other particles (IDL and VLDL) that are not absorbed by body tissues for metabolism can enter the vascular wall (particularly if it is already damaged by smoking, hypertension, or diabetes). Cholesterol accumulates in arterial linings to eventually form atherosclerotic plaques. This process leads to the progressive narrowing of blood vessels, resulting in claudication or angina and eventually plaque rupture, clot formation, and myocardial infarction or stroke. Cholesterol can be removed from tissues through the actions of HDL (reverse cholesterol transport) and transported to the liver for processing and conversion to bile.
Measured total cholesterol is the sum of cholesterol present in all lipid particles, including chylomicrons. Total cholesterol, triglycerides, and HDL are measured directly in common laboratory tests. Because of the cost, LDL is usually calculated by using measures of the other three, or it can be directly measured. Total cholesterol and HDL vary little with respect to fasting status; however, triglycerides vary widely. VLDL is estimated to be one-fifth of total triglyceride concentration, as long as triglycerides are <400 mg/dl (28). The formula (equation 1) for approximating LDL concentration (known as the Friedewald formula) is as follows (TC is total cholesterol, cLDL is calculated low-density lipoprotein cholesterol, TG is triglyceride concentration, and HDL is high-density lipoprotein cholesterol):
cLDL ≈ TC − HDL − VLDL (1)
VLDL is almost equal to triglycerides divided by 5. Therefore, substituting VLDL for TG/5 allows approximation of LDL concentration (cLDL) with TC, HDL, and TG concentrations (equation 2):
cLDL ≈ TC − HDL − triglycerides/5 (2)
Because of this principle, LDL can be calculated from a fasting patient by subtracting HDL and triglycerides divided by 5 from the value for total cholesterol, which yields what is known as the cLDL (calculated LDL). At lower triglyceride concentrations, IDL and chylomicrons make up an exceedingly small fraction of total cholesterol and are not measured. Because of fluctuations in triglyceride levels, specimens from nonfasting patients cannot be used to reliably estimate cLDL (29).
Well-established studies have linked cLDL, total cholesterol, and HDL (inversely) to rates of cardiovascular disease mortality, independent of other risk factors (4). There is evidence that reducing cLDL, especially among adults with moderate to high risk of cardiovascular disease, results in significant reductions (up to 50%) in death or myocardial infarction after treatment (30).
Non-HDL cholesterol, defined as serum total cholesterol minus HDL, appears to represent the portion of total cholesterol most clearly related to overall cardiovascular disease risk. Measured or cLDL may not accurately represent cardiovascular disease risk for persons with even modestly elevated triglycerides and could lead to undertreatment. This is especially true for persons with metabolic syndrome or exposure to second-generation antipsychotics. Guidelines for the treatment of non-HDL cholesterol are achieved through the same diet, lifestyle, and pharmacotherapy options as for LDL therapy and may represent a better treatment target than cLDL values for persons with severe and persistent mental illness. Treatment targets for non-HDL cholesterol are typically set 30 mg/dl higher than LDL goals and may be a surrogate benchmark for nonfasting patients. Although current guidelines favor the use of cLDL targets in initiating and measuring therapy, the use of nonfasting non-HDL cholesterol as a therapy target may offset challenges in arranging for follow-up fasting specimens among persons with severe and persistent mental illness.
Screening among persons with persistent mental illness
For adults in the general population, screening for dyslipidemia every five years is recommended. Current guidelines from the U.S. Preventive Services Task Force recommend screening men who have an average risk of cardiovascular disease every five years beginning at age 35 and screening women who have an average risk beginning at age 45. Adults with elevated risk, as defined by either a cardiovascular disease risk-equivalent (a ten-year risk of about 20% for major myocardial infarction, stroke, or death; or the presence of diabetes, preexisting cardiovascular disease, abdominal aortic aneurysm, peripheral arterial disease, or carotid artery stenosis) or a major risk factor (hypertension, myocardial infarction for a male first-degree relative by age 55 or a female first-degree relative by age 65, smoking, and HDL<40 mg/dl), should be screened beginning at age 20 (class B recommendation: there is moderate to high certainty that the net benefit is moderate to substantial) (31). By some estimates, these criteria would include up to 60% of persons seen annually at community mental health centers (32,33), regardless of antipsychotic use. There is evidence of a markedly elevated risk of diabetes or cardiovascular disease independent of exposure to second-generation antipsychotics among persons with severe and persistent mental illness (34,35).
The consensus conference of the American Diabetes Association and the American Psychiatric Association recommended that patients who are taking second-generation antipsychotics undergo screening for dyslipidemia (36). [A table summarizing the recommendations is available online as a data supplement to this article.] Some experts now recommend cholesterol screening every six months for individuals taking second-generation antipsychotics after one year of treatment if baseline or follow-up serum cLDL or non-HDL concentration is greater than 130 mg/dl or 160 mg/dl, respectively (37,38).
Rarely is the triglyceride level greater than 500 mg/dl, at which point it is associated with an increased risk of pancreatitis. Combined with checking hemoglobin A1C as a diagnostic indicator of diabetes (39), screening for dyslipidemia with non-HDL cholesterol may now be offered to nonfasting clients without the inconvenience of their having to return later for a fasting measurement (40). Individuals who screen positive for dyslipidemia (total serum cholesterol >200 mg/dl for males and females, HDL <40 mg/dl for males and <50 mg/dl for females, or triglycerides >500 mg/dl for males and females) should undergo follow-up fasting measurement of triglycerides and cLDL to guide interventions and referrals. Direct or add-on LDL measurement is a possibility, but it has not been rigorously evaluated in large epidemiologic studies, and there is some variance in laboratory assay standards.
Diagnosis and therapeutic targets of dyslipidemia
Elevated total cholesterol and low HDL cholesterol.
The following recommendations are based largely on Adult Treatment Panel III (ATPIII) guidelines of the National Cholesterol Education Program (NCEP) (4), which were last revised in 2004. Total cholesterol values >240 mg/dl have consistently been recognized as high, and values >200 mg/dl generally indicate an intermediate risk that requires fasting LDL measurement or the use of non-HDL cholesterol as the treatment target. HDL measurements of <40 mg/dl for males or <50 mg/dl for females warrant intervention, whereas HDL values >60 mg/dl have been recognized to lower an individual's risk of cardiovascular disease.
Triglycerides and the metabolic syndrome.
Fasting triglycerides have been associated with cardiovascular disease and remain a component in the diagnosis of metabolic syndrome. [A table summarizing metabolic syndrome criteria is available online as a data supplement to this article.] However, fasting triglyceride levels may be of less value than total cholesterol, LDL, and low HDL concentrations in predicting development of cardiovascular disease (40,41). For this reason, the primary goal of therapy is reduction of cLDL and elevation of HDL, reserving dedicated treatment of triglycerides to concentrations >500 mg/dl. For fasting triglyceride levels between 150 mg/dl and 500 mg/dl, interventions are first targeted at lowering LDL and subsequently non-HDL cholesterol (total cholesterol minus HDL cholesterol). After appropriate non-HDL cholesterol targets are obtained, there is little evidence to support targeted drug treatment of triglyceride levels <500 mg/dl.
NCEP ATPIII guidelines use an individual's cardiovascular risk and current cLDL levels to define treatment modalities and cLDL targets (4). Cardiovascular risk can be assessed as the number of major risk factors (as defined previously), with three levels defined as 0 to 1 (low), ≤2 (medium), or the presence of cardiovascular disease (high). Risk can also be calculated as ten-year risk of heart attack or death from cardiovascular disease on the basis of the Framingham Heart risk equation. To calculate an individual's Framingham Risk Score, online tools are readily available (hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof), and tools are also embedded in electronic health records. The Framingham equation gives a risk score that can be divided into three different categories—0%–10% (low), 10%–20% (medium), and >20% (high)—and is useful only in guiding therapy targets for individuals without cardiovascular disease risk-equivalent but with two or more clinical risk factors. Certain diagnoses (mainly preexisting cardiovascular disease or diabetes mellitus) automatically place individuals in the high-risk (>20%) category, because persons with these diagnoses are considered to have the same or higher risk as those with existing known cardiovascular disease (a “risk-equivalent”).
Table 1 lists cLDL and non-HDL targets for the three clinical levels of risk. Each higher risk level lowers thresholds and goals by 30 mg/dl. For persons in the highest risk group (Framingham risk >20%, cardiovascular disease, or coronary risk-equivalent), thresholds for starting medications are cLDL >100 mg/dl or non-HDL >130 mg/dl after three months of failed intensive diet and exercise therapy.
Since the publication of the NCEP ATPIII guidelines, several trials have demonstrated the benefits of lowering LDL to <70 mg/dl in some instances. An update to the NCEP guidelines in 2004 suggested that patients with diabetes or cardiovascular disease may benefit from further lowering of cLDL (42). This would be particularly important in cases of a recent cardiovascular event (past year) or if diabetes or cardiovascular disease is combined with other, poorly controlled risk factors (that is, smoking or metabolic syndrome), as is often the case among persons with severe and persistent mental illness.
Because cardiovascular disease risk increases in a linear relationship with LDL concentration, individuals at high clinical risk who have relatively low LDL concentrations may still benefit from lipid-lowering pharmacotherapy. Some countries (Canada and the United Kingdom) have proposed guidelines for treatment based on total ten-year risk scores and clinical data regardless of LDL levels (43), in part to simplify screening and minimize costs. This emerging trend argues strongly for aggressive attention to dyslipidemia in the population with severe and persistent mental illness and favors a low threshold for treatment based on existing guidelines.
Treatment of dyslipidemia
Broadly defined, treatment of dyslipidemia is aimed at lowering LDL and non-HDL and raising HDL through therapeutic lifestyle changes, pharmacotherapy, or both.
Diet and lifestyle interventions designed to reduce cardiovascular risk are often effective in reducing total cholesterol and LDL by up to 10%, but they usually involve resource-intensive (costly, labor-intensive) nutritional changes or exercise regimens that can be challenging to implement (44–50). Several factors may make these interventions particularly burdensome for persons with severe and persistent mental illness, including poor socioeconomic status, access to adequate facilities for safe exercise, concomitant medications that affect metabolism and sap energy, and lack of knowledge about nutrition and diet (38,51,52). Nevertheless, targeted recommendations and guidance from health professionals have been shown to assist persons with severe and persistent mental illness to lose weight and improve lipoprotein profiles (53–55), and they should be offered routinely.
Table 2 presents basic recommendations in the areas of diet and exercise that have been shown to improve cholesterol profiles. Routine dietary interventions involve the elimination of saturated and trans fats from the diet (56). Common sources of saturated fats include butter, cream, cheese, lard, coconut oil, palm oil, and chocolate. Common sources of trans fats include partially hydrogenated vegetable oils (most famously Crisco) that are commonly found in the fast-food industry in the production of fried foods and baked goods. Interventions that combine various components of exercise, dietary additives (such as omega-3 fatty acids and red-yeast extract), and fat reduction have been shown to be highly effective for some people, achieving up to a 35% reduction in LDL, which is similar to that achieved by therapy with some statins (56,57). More recently, newer approaches have been tested that include additional nutritional components that lower circulating LDL. These “portfolio” diets consist of a combination of soluble fiber, soy protein, tree nuts, and plant sterols (in margarine), have good adherence after just two dietary counseling sessions, and demonstrate robust lowering of cLDL compared with a diet of increased fiber and reduced saturated fat (reductions of 13% compared with 3% at six months) (58).
Exercise, defined as moderate aerobic exercise of around 120 minutes per week, has been shown to elevate HDL by up to 9% (approximately 3 mg/dl) and lower LDL, total cholesterol and triglycerides by up to 11%. Although modest increases in moderate-intensity exercise routines may not change LDL significantly, reports indicate that any structured physical activity may be beneficial beyond its cholesterol-lowering effects (52,59).
Table 3 lists medications used to manage dyslipidemia and the relative effect on cholesterol lowering in each category, as well as side effects during treatment. Before initiation of pharmacotherapy for treatment of dyslipidemia, consideration should be given to switching to an alternative antipsychotic, such as aripiprazole or ziprasidone, if indicated (22,60,61). Results of switching studies should be scrutinized for the role of funding in outcomes and the relative paucity of data supporting use of first-generation antipsychotics.
Studies examining the role of adjunctive pharmacologic weight-loss therapies, including metformin, ramelteon, topiramate, and others, have been reviewed elsewhere and are generally focused on attenuation of weight gain (62–64). Some limited evidence exists for topiramate, metformin, and ramelteon in improving cholesterol profiles of persons treated with antipsychotics.
Generally, statins are the first-line agents for treatment of most dyslipidemias. This approach is supported by several trials demonstrating significant reduction in nonfatal myocardial infarction and cardiovascular events among white and nonwhite patients receiving statin treatment (65–69). Studies evaluating statin use systematically among persons with severe mental illness are limited but generally positive and have found rates of adherence to treatment and outcomes similar to those in the general population (70,71).
Liver transaminases should be monitored at the initiation of therapy at three months, but only annually thereafter in the presence of comorbid liver disease. With adequate supervision, statins have been used safely for persons with comorbid liver disease (hepatitis C, in the absence of alcohol consumption or end-stage liver disease) as long as total transaminase levels do not increase more than threefold above established patient baselines (72). Myalgias are a common side effect and may be underreported, occurring for up to 10% of those on statin therapy. Life-threatening rhabdomyolysis is a very rare occurrence (73). Individuals who experience myalgias should have their statin held and creatinine kinase (CK) levels checked. Those with CK elevations less than tenfold over normal and without evidence of rhabdomyolysis (myoglobinuria) may safely be rechallenged with pravastatin or fluvastatin, both considered to have less overall muscle toxicity.
Statin medications are pregnancy category X and should be prescribed to women of childbearing age only after appropriate informed consent. In addition, simvastatin coadministered with risperidone has been associated with rhabdomyolysis and should be used with caution by persons taking tricyclic antidepressants for risk of higher antidepressant levels and QTc prolongation (74). Although mood stabilizers are generally safe, carbamazepine may induce hepatic metabolism and lower the efficacy of many statins. Because many psychiatric medications are metabolized through the CYP450 enzyme system, pravastatin should be considered a first-line treatment for lower-risk patients who do not need substantial cLDL or non-HDL reductions. Pravastatin is relatively more hydrophilic and has a dual metabolism that does not depend solely on liver or kidney function (75).
Some statin medications are readily available as generics (atorvastatin, lovastatin, pravastatin, simvastatin), which makes cost less of a barrier to access. Dosages should be titrated as tolerated to achieve adequate reductions in cLDL or non-HDL. Current evidence suggests that high-dose simvastatin (80 mg daily) is associated with an unacceptable risk of myositis and is generally avoided in practice (76); however, lower doses seem safe. High-dose rosuvastatin has been found to cause impaired renal function and may contribute in small amounts to the development of diabetes. Because of this, creatinine and hemoglobin A1C should be monitored at least yearly among patients taking this drug.
Because the majority of hepatic cholesterol synthesis occurs in the nighttime during fasting, statins with short half-lives (simvastatin, lovastatin, and pravastatin) should be administered in the evening. Certain statins with long half-lives (atorvastatin and rosuvastatin) may be dosed variably throughout the day without reduction in efficacy (77). If patients do not achieve cLDL goals with appropriately titrated statin treatment, a switch to a more potent statin, such as atorvastatin or rosuvastatin, may be recommended.
Treatment of hypertriglyceridemia (>500 mg/dl) and mixed dyslipidemia starts with a statin alone. Statin therapy lowers triglyceride levels among patients with schizophrenia (70). If triglyceride levels remain substantially abnormal (>500 mg/dl) with statin treatment, additional drugs may be used, such as fish oil, niacin, or fibrates in order of preference. When added to a statin, fenofibrate is the fibrate of choice, primarily because of increased risk of myositis with gemfibrozil. A specialist should manage augmentation strategies for lipid reduction, and referral is indicated if monotherapy is insufficient to improve the cholesterol profile.
Figure 1 presents a summary flowchart of screening and treatment guidelines. Persons with dyslipidemia who are on cholesterol-lowering therapy should have their cholesterol checked at least yearly, once stabilized, to demonstrate continued treatment success.