Polygenic Hypercholesterolemia Treatment & Management
- Author: Elena Citkowitz, MD, PhD, FACP; Chief Editor: George T Griffing, MD more...
Medical Care
During the 1990s, the cholesterol revolution occurred. Numerous studies documented the efficacy of low-density lipoprotein cholesterol (LDL-C) reduction in the reduction of coronary heart disease (CHD) events and, in some situations, the reduction of CHD and total mortality rates.
Medical therapy involves lifestyle modification and pharmacologic therapy.
For patients with known atherosclerosis (clinical CHD, symptomatic carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm), the LDL-C goal is less than 100 mg/dL, although an LDL-C goal of less than 70 mg/dL is now considered a therapeutic option in patients considered to be at very high risk (acute coronary syndrome patients, diabetes mellitus, multiple risk factors with uncorrected risk factors such as continued smoking).
For patients with 2 or more risk factors, the LDL-C goal is less than 130 mg/dL, with recommendations for drug therapy that depend on the estimated 10-year risk of a CHD event based on the modified Framingham equation (see below).
For patients at low risk (0-1 risk factors), the LDL-C goal is less than 160 mg/dL.
The LDL-C goal for patients with CHD equivalent risk, including patients with diabetes mellitus, should also be less than 100 mg/dL. In patients considered to be very high risk, a goal of less than 70 mg/dL is an acceptable option
The evaluation generally begins with a risk-factor analysis. Patients are then categorized according to CHD or CHD risk equivalent (particularly diabetes), ie, those with multiple risk factors and those at low risk (< 2 risk factors). Patients with CHD or CHD equivalent risk have a greater than 20% 10-year risk for CHD events. Low-risk patients generally have a 10-year CHD risk of less than 10%. Patients with multiple risk factors may or may not be at high risk.
The new National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines recommend calculating a Framingham risk score in patients with multiple risk factors to quantify risk and set LDL-C goals. The Framingham score calculator is available through the NCEP and the US National Heart, Lung, and Blood Institute (see Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD).
The European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) have also released guidelines for the management of dyslipidemias, available at the ESC site.[10]
Patients with CHD or CHD equivalent are prescribed drug therapy simultaneously with therapeutic lifestyle changes if their LDL-C concentration is greater than or equal to 130 mg/dL. Drug therapy is optional for patients whose LDL-C value is 100-129 mg/dL.
For patients with multiple risk factors, the LDL-C level at which drug treatment is recommended depends on the Framingham score. The LDL-C goal is less than 130 mg/dL. For patients with multiple risk factors and a 10-year risk of greater than 20%, the treatment is similar to that of patients with CHD. For patients with a 10-year risk of 10-20%, drug treatment is considered if their LDL-C level is greater than or equal to 130 mg/dL. For patients with multiple risk factors and a 10-year risk of less than 10%, drug therapy is considered if their LDL-C levels are greater than or equal to 160 mg/dL.
For patients at low risk, the LDL-C goal is less than 160 mg/dL, with therapeutic lifestyle changes for patients with higher values and drug therapy considered at LDL-C levels of greater than or equal to 190 mg/dL.
Therapeutic lifestyle treatment (ie, dietary changes and exercise) is recommended for patients whose LDL-C concentrations are greater than their goal LDL-C.
The new NCEP guidelines also recommend trying to identify patients with what has been called the metabolic syndrome. Such patients in particular should be targeted for therapeutic lifestyle changes. These patients meet at least 3 of the following criteria:
- Abdominal obesity (waist >40 in for men, >35 in for women)
- High triglyceride level (≥150 mg/dL)
- Low high-density lipoprotein cholesterol (HDL-C) value (< 40 mg/dL for men, < 50 mg/dL for women)
- High blood pressure (≥130/85 mm Hg)
- Impaired fasting glucose (IFG) value (plasma glucose level ≥110 mg/dL, although the lower limit now generally used in the American Diabetes Association IFG cutpoint of 100 mg/dL or greater)
If the patient's serum triglyceride level remains greater than or equal to 200 mg/dL after the LDL-C goal is reached, a secondary non–HDL-C goal is set. The non–HDL-C goal is the LDL-C goal plus 30 mg/dL. This goal may be achieved with an increase in the statin dose, a more efficacious statin, or the addition of another agent (eg, fibrate, niacin, fish oil). Fenofibrate has less of a propensity for drug interactions; therefore, it is preferred in most situations. If fish oil is used, the correct dose is at least 2-3 g of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) daily. Because most 1-g fish oil capsules contain only approximately 300 mg of DHA and EPA, a patient must consume 10 1-g fish oil capsules daily to reach the goal. More highly concentrated fish oil capsules or liquids can be used, but the patient usually cannot find these in local pharmacies.
Screen all patients via a fasting lipid profile every 5 years beginning at age 20 years. Patients with CHD should undergo a lipid profile determination at least yearly. Patients with multiple risk factors should have their lipid profiles determined at least every other year.
In 3 months, recheck the lipid profiles of patients treated with therapeutic lifestyle intervention. In 6-12 weeks, recheck the lipid profiles of patients treated with drugs.
Liver function testing is indicated periodically for patients taking statins or fibrates, although the risk for hepatotoxicity is very low. Liver function abnormalities are more common at the highest doses of each of the approved statins. Checking liver test results 6-12 weeks after an increase in the dose is reasonable, particularly in patients on high-dose statins.
The dosage and approximate LDL-C lowering of various statins is as follows:
- For atorvastatin at 10-80 mg/d, the LDL-C level is lowered by 39-60%.
- For fluvastatin at 20-80 mg every bedtime or 40 mg twice daily, the LDL-C level is lowered by 22-36%.
- For lovastatin at 20-40 mg every evening or 40 mg twice daily, the LDL-C level is lowered by 24-42%.
- For pravastatin at 10-80 mg every bedtime, the LDL-C level is lowered by 22-34%.
- For rosuvastatin at 5-40 mg/d, the LDL-C level is lowered by 45-63%.
- For simvastatin at 20-80 mg every bedtime, the LDL-C level is lowered by 38-47%.[11] In June 2011, a labeling change was made to warn physicians not to prescribe simvastatin in a dose that exceeds 40 mg/d (unless the patient has been taking 80 mg/d for at least a year without evidence of myopathy).
Statin intolerance creates a treatment dilemma for patients and practitioners in terms of selecting therapeutic options to treat hypercholesterolemia. Red yeast rice is an herbal supplement known to decrease LDL-C levels. Becker et al randomly assigned 62 patients (1:1 ratio) who discontinued statin therapy because of myalgias to receive either red yeast rice (1800 mg) or placebo twice daily for 6 months.[12] During the study, all patients also took part in a 12-week therapeutic lifestyle change program.
LDL-C levels were significantly lower in the red yeast rice group compared with the placebo group at 12 weeks and 24 weeks (P < 0.001 and P=0.011, respectively). Compared with the placebo group, the red yeast rice group also had a significant decrease in total cholesterol levels at 12 weeks and 24 weeks (P < 0.001 and P=0.016, respectively).
The study was small, but the results indicated that red yeast rice, along with a therapeutic lifestyle change, lowers LDL-C and total cholesterol levels. (It should be noted that red yeast rice contains a small amount of lovastatin.) Additional study is warranted to examine treatment alternatives for statin intolerance.
Therapeutic controversies
Post hoc analysis of some studies (eg, Cholesterol and Recurrent Events, West of Scotland Coronary Prevention Study[13] ) has been interpreted to indicate the presence of a lower limit for LDL-C, and, beyond this level, lowering the LDL-C is no longer beneficial. Similar analyses of other studies (eg, Scandinavian Simvastatin Survival Study,[14, 15] Air Force/Texas Coronary Atherosclerosis Prevention Study[16] ) have failed to indicate an LDL-C therapeutic threshold.
The Medical Research Council/British Heart Foundation Heart Protection Study enrolled subjects at high risk for CHD and total cholesterol (not LDL-C) concentrations greater than 135 mg/dL. CHD event reduction was observed in the total patient population and in the subgroup with the lowest tertile of LDL-C.
The completed Pravastatin or Atorvastatin Evaluation and Infection Therapy trial showed CHD event reduction when postacute coronary syndrome patients were treated with atorvastatin at 80 mg/d (LDL-C level at treatment was approximately 62 mg/dL) compared with pravastatin at 40 mg/d (LDL-C level at treatment was approximately 95 mg/dL). The study was plagued by high dropout (approximately one third of subjects in both groups at 2 y), and the fact that liver function test abnormalities (transaminase levels >3 times the upper limit normal) were common. The number needed to treat to prevent a CHD event was 26, and the number needed to treat to potentially harm (transaminases >3 times the upper limit normal) was 45.
The Post Coronary Artery Bypass Graft Trial showed less progression of the disease in bypass grafts with attainment of an LDL-C value of approximately 95 mg/dL (achieved with lovastatin) compared with less aggressive treatment, with an LDL-C value of approximately 135 mg/dL.[17]
The Reversal of Atherosclerosis with Aggressive Lipid Lowering trial showed minimal regression of atherosclerosis in CHD subjects treated with 80 mg of atorvastatin for 18 months compared with minimal progression in CHD subjects treated with 40 mg of pravastatin.
The Atorvastatin versus Revascularization Treatment trial showed no difference in CHD events in patients treated to achieve an LDL-C level of approximately 77 mg/dL compared with patients with an LDL-C level of approximately 115 mg/dL who had angioplasty.[18]
The Treating to New Targets Study showed a reduction in cardiovascular events, but not mortality, in patients with stable CHD who were given atorvastatin 80 mg/d compared with atorvastatin 10 mg/d (LDL-C 77 mg/dL vs 101 mg/dL). Persistent transaminase elevations were 6 times as common in the former group.
Because the epidemiologic data suggest a curvilinear relationship between LDL-C values and CHD events, an LDL-C level below which no benefit may accrue is probable; however, that actual level is unknown. The National Cholesterol Education Program (NCEP) guidelines probably provide an adequate estimate of an appropriate LDL-C target, except perhaps in patients with diabetes.
The author believes that lower targets (< 70 mg/dL) may be reasonable in patients who can be treated with low-to-moderate dose statin. However, the author feels that the risk/benefit ratio for high-dose statin (atorvastatin 80 mg/d is what has been tested so far) across the board to try to achieve an LDL-C level of less than 70 mg/dL (many patients will not achieve this level despite this therapy) is not yet proven definitely to be acceptable and achieve extra added benefit. The question of achieving lower LDL-C values with combination therapy (statin plus ezetimibe), in terms of showing further CHD risk reduction, remains unanswered at this point.
Whether patients with low HDL-C and high LDL-C values should use a drug (eg, niacin) to raise their HDL-C levels, in addition to using a drug to lower LDL-C levels, is questionable. The HDL Atherosclerosis Treatment Study showed positive effects of low-dose (10 mg) simvastatin and niacin on angiographic measures. However, no outcome studies have been performed with more conventionally used doses of statins. Statins often raise HDL-C levels a small amount. Some statin trials show a marked diminution of increased CHD risk in patients treated with statins who have lower HDL-C levels compared with individuals with higher HDL-C levels. The results of the Veterans Affairs HDL Intervention Trial may not be applicable to patients with high baseline LDL-C concentrations.
Patients with mixed dyslipidemias
Patients with insulin resistance and those with type 2 diabetes mellitus are likely to have mild-to-moderate triglyceride elevations.
Whether lipid therapy beyond statins is beneficial is debatable, although combination therapy with statins plus niacin or fibrates improves lipid parameters. Such therapy clearly increases the potential for adverse effects. The author believes that most patients should be treated with monotherapy. If a fibrate is given with a statin, fenofibrate is probably safer than gemfibrozil.
A potentially more benign nutraceutical is fish oil. Omega-3-acid ethyl esters are currently FDA-approved for hypertriglyceridemia. The omega-3-acid ethyl esters eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglyceride levels if at least 3 g per day is administered. Unfortunately, many preparations contain large amounts of fish oil that is not DHA or EPA. These preparations just supply fat, with little positive effect on the lipid profile. The physician can avoid this problem by personally examining the bottle of fish oil that his or her patients will be using.
Women who are postmenopausal
Although epidemiologic studies have suggested that estrogen therapy is associated with better lipid profiles and lower CHD risk, recent intervention trials with estrogen have generated considerable controversy.
Currently, therapy with estrogens plus progestins is considered potentially harmful long-term therapy in postmenopausal women. This drug combination may still be useful for short-term therapy soon after menopause for vasomotor symptoms in women with an intact uterus.
In women who do not have a uterus, therapy with estrogen alone is of no proven benefit for CHD prevention.
Statin therapy, rather than estrogens, should be used for primary lipid modification and for CHD prevention in women who are postmenopausal, particularly in women with atherosclerosis.
Patients with diabetes
The post hoc analysis of the Scandinavian Simvastatin Survival Study trial in patients with type 2 diabetes mellitus showed dramatic event reduction in patients who received simvastatin. Unfortunately, this trial did not include patients with high triglyceride levels, which is a common lipid abnormality in persons with type 2 diabetes mellitus.[14, 15]
The Medical Research Council/British Heart Foundation Heart Protection Study (of simvastatin 40 mg/d) showed a similar reduction in CHD event rates in patients with type 2 diabetes mellitus compared with patients without diabetes.[15]
An extended follow-up of the Heart Protection Study examined the long-term efficacy and safety of LDLc-lowering with simvastatin treatment. In-trial cardiovascular benefits began after the first year and increased with each subsequent year of statin therapy and persisted 6 years beyond the end of the study. No difference in nonvascular morbidity or mortality was observed either during 5 years of statin therapy or in 6-year follow-up. The investigators recommend prompt initiation and long-term statin treatment in patients who are at increased risk for vascular events.[19]
Epidemiologic work suggests that patients with diabetes who have not had a previous known myocardial infarction may be at the same risk for CHD events and mortality as patients without diabetes who have had a previous coronary event. These data led the American Diabetes Association to advocate an LDL-C level of less than 100 mg/dL for patients with diabetes.
American Diabetes Association treatment based on LDL-C levels
In patients without coronary heart disease, peripheral vascular disease, or cardiovascular disease who have an LDL-C level of greater than 100 mg/dL, the goal level of LDL-C is less than 100 mg/dL (< 70 mg/dL is considered an option).
In patients with coronary heart disease, peripheral vascular disease, or cardiovascular disease who have an LDL-C level higher than 100 mg/dL, the goal level of LDL-C is less than 100 mg/dL (< 70 mg/dL is considered an option).
In patients without coronary heart disease, peripheral vascular disease, or cardiovascular disease who have an LDL-C level higher than 130 mg/dL, the goal level of LDL-C is less than 100 mg/dL. Additionally, for patients with diabetes who have multiple CHD risk factors (eg, low HDL-C level, hypertension, smoking, family history of cardiovascular disease, microalbuminuria or proteinuria), most authorities recommend drug therapy for LDL-C levels of 100-130 mg/dL. Age and sex are not risk factors because women and men have equal CHD risk.
In patients with CHD, peripheral vascular disease, or cardiovascular disease who have an LDL-C level of greater than 100 mg/dL, the goal level of LDL-C is less than 100 mg/dL (goal of < 70 mg/dL is an option).
The NCEP ATP III now considers diabetes mellitus a CHD risk equivalent, with the same LDL-C goal (< 100 mg/dL, or, if considered appropriate, < 70 mg/dL) as patients with known CHD have.
With statin monotherapy, the risk of myopathy is low, but it is increased with the concomitant use of fibrates, niacin, macrolides, protease inhibitors, and imidazoles. The fibrate effect appears to relate to inhibition of glucuronidation of statins, rather than an effect on cytochrome P450 metabolism, because it is observed with all statins.
Routine CK monitoring has no proven value in the prevention of myopathy. Because muscle aches are common, even in placebo-treated patients, a check of serum CK values, once the patient has myalgias, may be helpful. Many patients with myalgias have CK values within the reference range.
Sometimes, changing the statin is necessary to eliminate the problem. Anecdotal reports suggest that coenzyme Q supplements in patients with muscle aches and CK values within the reference range may reduce myalgias.
Reports suggest that histologic myopathy may occur in the absence of CK elevations. Whether this is a widespread phenomenon is debatable.
Diet
The NCEP has created dietary guidelines for all people older than 2 years. The reduction of saturated fat intake is vitally related to reduced low-density lipoprotein cholesterol (LDL-C) levels. In general, replacing fat with complex carbohydrates is helpful. Because carbohydrates are less calorically dense than fat, this substitution may also help prevent obesity. Adopting an appropriate diet may help patients reduce their LDL-C value by approximately 10-15%.[6] However, in real-world studies, a 5% reduction is more likely. Reduction in trans fat intake also helps to reduce LDL-C levels and may help to raise high-density lipoprotein cholesterol (HDL-C) levels.
NCEP dietary guidelines are as follows:
- Total fat - Less than 30% of energy intake (calories)
- Saturated fat - Less than 7% of energy intake
- Polyunsaturated fat - Less than or equal to 10% of energy intake
- Monounsaturated fat - From 10-15% of energy intake
- Cholesterol - Less than 200 mg/dL
- Carbohydrates - From 50-60% of energy intake
Extreme fat and cholesterol restriction has been achieved with vegetarian diets, as demonstrated by the 1990 studies performed by Ornish and colleagues. This type of dietary restriction has resulted in a marked reduction in LDL-C levels and improvement in CHD symptoms. Whether these dietary restrictions are realistic for most Americans is debatable. Moreover, such a diet also reduces HDL-C levels and raises triglyceride levels.
Plant sterols and plant stanol esters can be included in the diet and may reduce LDL-C values by approximately 10-15%. Commercial preparations are available as margarine substitutes (eg, Benecol, Take Control).[7]
After years of lay promotion, small, short-term (6 mo) studies have suggested that high-fat, low-carbohydrate diets (eg, the Atkins diet) may facilitate weight loss without adversely affected serum lipid concentrations. However, the long-term effects of such diets remain to be determined.
A study by Jenkins et al found that use of a dietary portfolio resulted in greater LDL-C reduction compared with low-saturated fat dietary advice over 6 months in patients with hyperlipidemia.[20]
Activity
Although exercise has little effect on low-density lipoprotein cholesterol (LDL-C) concentrations, aerobic exercise may improve insulin sensitivity, high-density lipoprotein cholesterol (HDL-C) concentrations, and triglyceride levels and, thus, may help reduce CHD risk. Patients who exercise and adhere to an appropriate diet appear to be more successful in long-term lifestyle modifications that improve their CHD risk profile.
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