Management of elevated blood cholesterol in the psychiatric patient: What's new in the guidelines?

INTRODUCTION

Compared with the general adult population, patients with schizophrenia and bipolar disorder have a 1.5 to 2.8 fold increase in mortality rates.¹ The increase in mortality is multifactorial, including both natural causes and suicide.^1–5 One contributing factor is that individuals with psychiatric illness often have lifestyles associated with poor self-care, substance abuse, obesity, and lack of medical care. Additionally, it is well-known that current antipsychotic treatments are implicated in weight gain, the onset of diabetes, increases in lipid levels, and QT prolongation.^6–9 Each of these adverse effects places patients with schizophrenia and bipolar disorder at added risk for metabolic syndrome or cardiovascular events. Because of this increased risk of morbidity and mortality, regularly monitoring the physical health of a patient with schizophrenia or bipolar disorder is of equal importance as monitoring their mental health. This review article will focus on the newly published guidelines from the American College of Cardiology/American Heart Association for the management of blood cholesterol to reduce atherosclerotic cardiovascular risk.¹⁰ Recent clinical trials of hyperlipidemia, international hyperlipidemia guidelines, and changes from the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines will also be discussed.¹¹¹²

Hyperlipidemia is considered a powerful predictor of atherosclerotic cardiovascular disease (ASCVD). The new guidelines discuss the treatment of blood cholesterol levels to reduce ASCVD, which includes coronary heart disease (CHD), stroke, and peripheral artery disease. Several clinical trials have found a direct relationship between elevated low density lipoprotein (LDL) cholesterol, coronary atherosclerosis, and CHD.¹¹ It has been well-established that the higher the level of LDL, the greater the risk of cardiovascular events such as myocardial infarction. A 10% increase in cholesterol level is associated with a 20–30% increase in the risk of CHD.¹³ Further, cardiovascular diseases, including CHD, are the number one cause of death worldwide.¹⁴ In light of this risk, and the increased risk of hyperlipidemia in individuals with schizophrenia and bipolar disorder, an understanding of how to evaluate and treat hyperlipidemia based on current evidence is crucial for health care providers.

WHEN TO EVALUATE?

The ACC/AHA guidelines recommend calculating estimated 10-year ASCVD risk every 4 to 6 years in individuals aged 40 to 75 years of age without clinical ASCVD or diabetes and with LDL 70 – 189 mg/dL.¹⁰ ATP III recommends that low risk patients above the age of 20 have a fasting lipid panel measured at least every 5 years.¹¹ More frequent evaluations are recommended for persons with multiple risk factors.

There are several major consensus documents that provide more specific recommendations for this patient population. One consensus was developed by psychiatrists and other medical experts that met in 2002 at the Mount Sinai School of Medicine in New York City with the goal of developing recommendations for the systematic health monitoring of individuals with schizophrenia and antipsychotics.¹⁵ In regards to hyperlipidemia, this group recommends that individuals with schizophrenia and prescribed antipsychotics be considered at high risk for CHD. In this regard, lipid screening should be obtained at least once every 2 years when the LDL level is normal and once every 6 months when the LDL level is greater than 130 mg/dl. If a patient's LDL level is greater than 130 mg/dl, the patient should be referred to a primary care provider.¹⁵ In 2004, the American Psychiatric Association (APA), the American Diabetes Association (ADA), the American Association of Clinical Endocrinologists (AACE), and North American Association for the Study of Obesity (NAASO) jointly developed guidelines that provide recommendations for the monitoring of metabolic problems associated with second generation antipsychotics (SGA).¹⁶ These guidelines recommend monitoring a fasting lipid profile at baseline, 12 weeks after initiation of a SGA, and then every 5 years, but note that more frequent assessments may be warranted based on clinical status.¹⁶

A second consensus More recently, the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes and the European Society of Cardiology, issued a position statement in 2009 on cardiovascular disease in patients with severe mental illness.¹⁷ It is their recommendation that cholesterol measurements should be taken at the initial presentation and before the first prescription of antipsychotic medication. For patients with normal baseline tests, it is recommended that measurements are repeated at 6 weeks and 12 weeks after initiation of treatment and at least annually thereafter. The frequency of testing will then depend on the patient's medical history and the prevalence of baseline risk factors.¹⁷

A fasting cholesterol panel is recommended specifically because LDL is a calculated value that can be erroneous in the setting of postprandial hypertriglyceridemia. Total cholesterol and high density lipoprotein (HDL) cholesterol are reliable in a non-fasting state.¹¹

Despite the minor differences in recommendations on when to monitor a patient's lipid profile, it is obvious that monitoring should occur on a regular basis. A practical approach to these recommendations would be to monitor a patient's fasting lipid profile at baseline, 12 weeks after initiation of a SGA, and then between every 6 months and every 2 years, based on the baseline LDL and the prevalence of other risk factors. At minimum, a patient's estimated 10-year ASCVD risk should be calculated every 4 to 6 years.

WHO DO WE TREAT?

The ACC/AHA task force found extensive and consistent evidence supporting the use of HMG CoA reductase inhibitors (“statins”) for the prevention of ASCVD in many higher risk primary and all secondary prevention individuals without NYHA class II–IV heart failure and who were not receiving hemodialysis. On the basis of this large body of evidence, 4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events.¹⁰ According to these guidelines, the following 4 groups of individuals should be considered eligible for statin treatment:

1. patients with clinical ASCVD

2. patients with primary elevations of LDL ≥ 190 mg/dL

3. patients with diabetes aged 40 – 75 years with LDL 70 – 189 mg/dL and without clinical ASCVD

4. patients without clinical ASCVD or diabetes, but with LDL 70 to 189 mg/dL and estimated 10-year ASCVD risk ≥7.5%.

Clinical ASCVD includes all secondary prevention patients, i.e. those with history of acute coronary syndrome, MI, angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease.

The 10-year risk of ASCVD is defined as the patient's risk for nonfatal MI, CHD death, fatal or nonfatal stroke in the next 10 years. This risk should be evaluated using the Pooled Cohort Equations available in the new guidelines.¹⁸ One critique of ATP III is its use of the Framingham Risk Score (FRS), which not only overlooks certain risk factors for CHD, but also only determines risk for nonfatal MI and CHD death versus other potential cardiovascular events such as stroke.¹⁹²⁰ Risk factors that the FRS does not use include metabolic syndrome and presence of chronic kidney disease. Though the FRS includes hypertension and tobacco use as risk factors, these conditions should be first managed with antihypertensives and tobacco cessation, prior to use of a lipid lowering agent.²⁰ Additionally, the FRS has not been used as enrollment criteria in major statin trials.¹⁹²⁰ These limitations cause ATP III to miss opportunities for protection in patients still at risk for ASCVD. In order to more closely estimate the total burden of ASCVD, the new guidelines recommend a comprehensive assessment of the estimated 10-year risk for an ASCVD event that includes both CHD and stroke.¹⁰ The risk calculator is available for download from: http://my.americanheart.org/cvriskcalculator.18

The calculator uses sex, age, race, total cholesterol, HDL, systolic BP, treatment for hypertension, diabetes, and smoking status to determine 10-year risk score and lifetime ASCVD risk. The calculator should be used in non-Hispanic Caucasian and African American men and women aged 40 – 79 years with or without diabetes who have LDL 70–189.

Of note, there is currently concern that the risk calculator over-estimates a patient's true ASCVD risk, therefore making more patients eligible for statins than may be necessary.²¹ The AHA has emphasized their support of the risk calculator and state that it will be updated as new data become available.²² Furthermore, they stress the need for patients and physicians to weigh the risks and benefits of statin therapy and individualize care based on the patient's profile. The decision to treat for primary prevention should be patient-centered and the potential for an ASCVD risk reduction benefit, adverse effects, and drug-drug interactions should be considered and discussed with the patient prior to statin initiation. As the new ASCVD risk calculator does not take into account family history of premature cardiovascular disease, body mass index, and lifestyle habits, these patient-specific factors should also be under consideration when determining whether or not to begin statin therapy.¹⁰²²

WHAT DO I TREAT WITH?

First line treatment for patients with hyperlipidemia is always therapeutic lifestyle changes (TLC).¹⁰¹¹ TLC should be emphasized throughout treatment and includes a heart healthy diet, weight management, tobacco cessation, and increased physical activity. Physical activity should include 30 minutes of moderate intensity activity, most days of the week, and could include brisk walking, bicycling, or swimming. TLC is recommended for all patients with lifestyle-related risk factors such as obesity, physical inactivity, elevated triglycerides, low HDL, or metabolic syndrome.

The most recent literature highlights the benefits of statins and recommends utilizing statins over other drug classes, for both primary and secondary prevention of CHD.¹⁹ The ACC/AHA guidelines also endorse statin use and do not encourage the use of other lipid-lowering agents. Statins have been studied more extensively than other lipid-lowering agents in randomized controlled trials and have shown benefit across a variety of patient populations, including as primary and secondary prevention, and in patients with stroke and chronic kidney disease.¹⁰¹⁹²³ Recent randomized controlled trials either compared fixed doses of statins with placebo or untreated controls, or compared fixed doses of higher-intensity statins with moderate-intensity statins. These trials were not designed to evaluate the effect of titrated (dose-adjusted) statin treatment to achieve pre-specified LDL or non-HDL goals. Therefore, the ACC/AHA Expert Panel was unable to find randomized controlled trial evidence to support titrating cholesterol-lowering drug therapy to achieve target LDL levels, as recommended by ATP III.¹⁰¹¹ Instead, therapy should be targeted based on the need for moderate-intensity statin therapy versus high-intensity statin therapy. Table 1 categorizes statins by the appropriate doses for the recommended intensity level. According to the ACC/AHA, the percent reduction in LDL can be used as an indication for response and adherence to therapy, but is not in itself a treatment goal.

Table 1. High-Moderate -and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the ACC/AHA Expert Panel)¹⁰

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Specific statins and doses that were evaluated in RCTs are noted in bold. Each of the studied RCTs demonstrated a reduction in major cardiovascular events. Statins and doses that are approved by the U.S. Food and Drug Administration but were not specifically tested in the reviewed RCTs are noted in parentheses and italics. Unless otherwise specified, dosing is once daily.

Table 2 matches specific patient populations with the recommended intensity of statin therapy.

Table 2. Recommendations for statin use in specific patient populations¹⁰

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According to consistent evidence, the absolute benefit in ASCVD risk reduction is proportional to the baseline risk of the patient group or individual, and to the intensity of statin therapy. Therefore, patients at higher baseline absolute risk will derive greater benefit from statin therapy over 5–10 years.¹⁰

WHAT ARE THE RISKS AND HOW DO I MONITOR THEM?

The new guidelines recommend against routine monitoring of creatine kinase (CK) in patients on statin therapy. However, CK should be measured in patients with muscle symptoms such as severe myalgias and myopathy. A baseline CK is reasonable in patients with a personal or family history of statin intolerance or muscle disease. Prior to initiating statin therapy, a history of prior or current muscle symptoms should be obtained in order to establish a baseline. Other conditions that might increase the risk for muscle symptoms (e.g. hypothyroidism, rheumatologic disorders, vitamin D deficiency) should be evaluated and ruled out.¹⁰ If patient cannot tolerate initial statin therapy, a lower dose, alternative statin, or every other day dosing should be tried before switching to another drug class.²⁴

Baseline measurement of hepatic transaminase levels (ALT, AST) should be performed before initiating statin therapy. If normal, further hepatic monitoring is not needed. Hepatic function tests should be performed if patient presents with symptoms suggesting hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of the skin or sclera).¹⁰

New onset diabetes associated with statin use has been reported in the JUPITER trial, several recent meta-analyses, and a Cochrane review.^25–30 These studies show an increased risk of between 9 – 18% for statin use compared to usual care or placebo, and with high dose versus usual dose statins.²⁵²⁹³⁰ This increased risk of diabetes has been associated with high baseline fasting glucose levels and symptoms of metabolic syndrome.³¹³² In this regard, the increased risk of incident diabetes appears to be confined to those with risk factors for diabetes. It would require treatment of 255 (95% CI 150–852) patients with statins for 4 years to see one extra case of diabetes, however, over this same time period, 5.4 coronary events would be prevented per 38.7 mg/dL reduction in LDL.³⁰ The small proportion of patients who develop diabetes is outweighed by the cardiovascular benefits of statins.^25–32

Individuals receiving statin therapy should be evaluated for new-onset diabetes mellitus according to the current diabetes screening guidelines.¹⁰³³ Those who develop diabetes mellitus during statin therapy should be encouraged to adhere to a heart healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD event.

In the newly published guidelines, the authors emphasize that the occurrence of a major CVD event (MI or stroke) represents a much greater harm to health status than does an increase in blood glucose leading to a diagnosis of diabetes.¹⁰

WHAT ARE MY PATIENT'S GOALS?

As mentioned above, ATP III set specific LDL goals for patients based on their cardiovascular risk factors.¹¹ The ACC/AHA guidelines raise concerns with targeting specific LDL goals based on the lack of clinical trial data to determine what goals should be. Randomized controlled trials (RCT) clearly show that ASCVD events are reduced by using the maximum tolerated statin intensity in those groups shown to benefit.¹⁰ No RCTs titrate drug therapy to a specific LDL goal of <100 mg/dL or <70 mg/dL to improve ASCVD outcomes. Trials of niacin and of a novel class of drugs (cholesterol ester transfer protein inhibitors) have not yet shown promise in reducing morbidity and mortality associated with CHD, despite decreases in LDL and increases in HDL.³⁴³⁵

Recent meta-analyses suggest that the primary goal for patients at high risk for vascular events should be to achieve the largest LDL cholesterol reduction possible, without significantly increasing the risk of myopathy.³⁶ In light of this evidence, the guidelines do not support titrating cholesterol-lowering drug therapy to achieve optimal LDL or non-HDL levels because the clinical trials were nearly all fixed dose trials. Overall, the treatment goal should be to maximize statin therapy.¹⁰

WHEN DO I FOLLOW UP?

After statin initiation, a follow up lipid panel should be performed 4 – 12 weeks later to determine adherence. After this initial follow up, clinicians should assess a patient's lipid panel every 3–12 months as clinically indicated. At follow up, clinicians should evaluate whether statin dose is optimized and if patient is tolerating the statin. At every visit, adherence to medication regimen and TLC should be assessed as both are critical to ASCVD risk reduction.¹⁰

CONCLUSIONS

Patients with schizophrenia and bipolar disorder are at higher risk of medical conditions such as diabetes and hyperlipidemia.^1–9 These conditions should be monitored, particularly when a patient is using an antipsychotic as part of their treatment.^15–16 The new ACC/AHA guidelines on treatment of hyperlipidemia should be considered when evaluating a patient for pharmacologic therapy. Recent literature suggests that even patients with a low baseline risk for CHD can benefit from statin use and will have reductions in cardiovascular mortality.^25–3236 Providers should consider statins for primary prevention as an adjunct to TLC in middle-aged and older individuals that fall into the major statin benefit groups.¹⁹²⁰ As always, providers should use their clinical judgment in weighing potential benefits, adverse effects, drug-drug interactions and patient preferences.¹⁰ All patients, including those with mental health disorders, should be counseled on therapeutic lifestyle changes such as healthy diet, exercise, and avoidance of substances such as tobacco. Though an increased risk of incident diabetes has been shown with statin use, the cardiovascular benefits far outweigh this risk. Considering the high burden of cardiovascular disease on health care today, health care providers in all fields can have a significant impact on patient care with increased awareness, monitoring, and treatment of hyperlipidemia.

Patient Case: PP is a 53 year old Caucasian female with a past medical history (PMH) of schizoaffective disorder, bipolar type; post-traumatic stress disorder (PTSD); and hypertension (HTN). PP's current medications include lurasidone 80 mg daily, topiramate 100 mg BID, carbamazepine 200 mg BID, prazosin 1mg QHS, fluphenazine decanoate 40 mg Q 3 weeks, and lisinopril 5mg daily. PP endorses smoking cigarettes, approximately 1 pack per day. PP's father is deceased secondary to experiencing a MI at age 67. PP's mother is alive with a PMH significant for HTN and Type 2 diabetes. Recent systolic blood pressures range from 130–150 mm HG, while diastolic blood pressure ranges from 74–93 mm Hg. PP's most recent lipid profile (fasting) results were total cholesterol = 223, triglycerides = 144, HDL = 42, and LDL = 149.

1. Does this patient have clinical ASCVD?

2. What is this patient's 10 year ASCVD risk?

3. Would you recommend starting treatment for hyperlipidemia in this patient?

4. If so, with what agent?

5. When would you follow up?

Answers:

1. No

2. Using online AHA/ACC Risk Calculator: 11.5%

3. Yes, patient's 10 year ASCVD risk is >7.5%

4. A moderate to high-intensity statin such as: atorvastatin 10mg q day, rosuvastatin 10mg q day, pravastatin 40mg q day, or fluvastatin 40mg BID. Other options may also be correct. See Table 1.

5. Follow up in 4–12 weeks, assess lipid panel, adherence, TLC.