Polygenic hypercholesterolemia is the most common cause of elevated serum cholesterol concentrations. Low-density lipoprotein cholesterol (LDL-C) elevations are moderate (140-300 mg/dL) with serum triglyceride concentrations within the reference range. However, practically speaking, the material in this article is also relevant to patients with mixed dyslipidemias with triglyceride levels of less than 350 mg/dL.
This condition is caused by a susceptible genotype aggravated by one or more factors, including atherogenic diet (excessive intake of saturated fat, trans fat, and, to a lesser extent, cholesterol), obesity, and sedentary lifestyle. The involved genes have yet to be discovered. Polygenic hypercholesterolemia is associated with an increased risk for coronary heart disease (CHD), as displayed in the image below.
View Image
Relative risk of coronary heart disease (CHD) mortality versus baseline serum cholesterol over time in 3 large cohorts of young men. CHA is Chicago He....
In the United States, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines are the most commonly used reference for determining therapeutic target LDL-C levels. The guidelines were first published in 1988 (ATP I),[1] with an update published in 2004.[2] The revisions and update have reflected the results of randomized placebo controlled clinical trials that have demonstrated reduced morbidity and mortality in subjects with moderate hypercholesterolemia treated with cholesterol-lowering agents, particularly (though not exclusively) statins.[3]
Low-density lipoprotein (LDL) particles are the major plasma carriers of cholesterol. Therefore, in patients with normal or minimally elevated triglyceride levels and average high-density cholesterol levels (HDL-C), the total serum cholesterol measurement can be used as a surrogate for the LDL-C level. Hypertriglyceridemia is caused by excessive numbers of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and/or chylomicron particles; and in this situation, the total cholesterol level is not a reflection of the LDL-C level. For a simplified diagram of cholesterol metabolism, see the image below.
View Image
Simplified diagram of cholesterol metabolism. LDL is low-density lipoprotein, VLDL is very low-density lipoprotein, IDL is intermediate-density lipopr....
Elevated LDL-C concentrations may be the consequence of elevated LDL production or decreased LDL hepatic uptake. The liver is responsible for high LDL-C levels, as follows:
Overproduction of VLDL particles, which are converted to VLDL remnants or IDL particles by lipoprotein lipase and then to LDL particles by hepatic lipase (which occurs with diet high in triglycerides), or
Inefficient uptake by the LDL receptors (Diets high in saturated fat, trans fat, and cholesterol cause a reduction in LDL receptors in the liver, thus retarding LDL catabolism.)[4, 5, 6, 7]
Familial hypercholesterolemia (FH) is sometimes clinically difficult to distinguish from polygenic hypercholesterolemia unless genetic testing is performed. The presence of mutations in the following genes has most often been studied in the spectrum of familial hypercholesterolemia[8, 9] :
Gene encoding the receptor for removal of LDL-C (LDL-R), 93%
APOB gene encoding for apolipoprotein B, 5%
PCSK9 gene (proprotein convertase subtilisin kexin 9), which codes for protein responsible for degradation of LDL receptor, 2%
A case-controlled study was done in the UK to determine if LDL cholesterol gene score can help differentiate patients with polygenic and monogenic familial hypercholesterolemia. It comprised more than 600 patients with clinical FH and 3,020 control subjects. The study attempted to distinguish patients with polygenic and monogenic FH by genotyping for the 3 known genetic causes above and 12 common LDL-C raising single-nucleotide polymorphisms (SNPs). Only about 50% of patients with clinical FH had monogenic FH, although many were found to have multiple SNPs. Multiple genetic mutations were often found in those labeled as having a polygenic cause.[10]
Some patients with mixed dyslipidemias (elevations of both LDL-C and triglycerides) may have polygenic hypercholesterolemia along with some other condition such as insulin resistance or obesity that causes high triglyceride values.
The guidelines of the American Heart Association and the NCEP Adult Treatment Panel III (ATP III) define hypercholesterolemia as a blood cholesterol concentration of 240 mg/dL or more. Desirable cholesterol concentrations are less than 200 mg/dL.
Based on data from the 2009-2012 National Health and Nutrition Examination Survey (NHANES), an estimated 73.5 million (31.7%) US adults aged 20 years or older has high LDL-C 130 mg/dL, but only 48.1% are treated and 29.5 % have their LDL-C controlled. A person with high LDL-C is defined as either a person whose LDL-C levels were above the LDL-C goal levels or a person who reported currently taking cholesterol-lowering medication. The proportion of adults with high LDL-C who are treated increased from 28.4% to 48.1% between the 1999-2002 and 2005-2008 study periods. Among adults with high LDL-C, the prevalence of LDL-C control increased from 14.6% to 33.2% between the periods.[11]
International
Serum cholesterol concentrations vary widely throughout the world. Generally, countries associated with low serum cholesterol concentrations (eg, Japan) have lower CHD event rates, while countries associated with very high serum cholesterol concentrations (eg, Finland) have very high CHD event rates. However, some populations with similar total cholesterol levels have very different CHD event rates, as would be expected given that other risk factors (eg, prevalence of smoking or diabetes mellitus) also influence CHD risk. The cholesterol levels in developing countries tend to increase as western dietary habits (McDonald's syndrome) replace traditional diets.
Race
Among adults, National Health and Nutrition Examination Survey data (2011-2012) showed higher LDL cholesterol level among Hispanic males (38.8%), than non-Hispanic black males (30.7%) than non-Hispanic white males (29.4%)
Sex
Elevated LDL-C is more common in females (32%) than in males (31%), based on National Health and Nutrition Examination Survey data (2011-2012).
Age
In adults, hypercholesterolemia increases with advancing age, as shown in the image below.
View Image
National Health and Nutrition Examination Survey data for hypercholesterolemia among American adults.
The primary consequence of hypercholesterolemia is increased CHD risk.[12] Data from epidemiological studies (eg, the Multiple Risk Factor Intervention Trial and the Framingham Heart Study) show a relationship between elevated LDL-C concentrations and CHD events and CHD mortality rates. In the prestatin era, randomized clinical trials showed a clear correlation between CHD morbidity and mortality but not total mortality. The advent of the statins, medications that are more easily tolerated and substantially more powerful than older cholesterol-lowering medications, increased the likelihood of substantial LDL-C lowering (increased power). Thus, the statins showed benefits that drugs used in previous studies had not.[13]
Placebo-controlled statin trials have demonstrated not only reduced coronary morbidity and mortality in primary and secondary prevention populations, but also decreased total mortality.
The causative relationship between LDL-C levels and ischemic stroke and transient ischemic attack (TIA) was suggested by decreased cerebrovascular events in several major statin trials in which stroke was a secondary endpoint. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study definitively showed that in patients who had suffered a recent stroke or TIA but who had no CHD, high-dose statin reduced the overall incidence of stroke and cardiovascular events despite a small, but statistically significant, increase in the incidence of hemorrhagic stroke.[14, 15]
Statins have revolutionized the treatment of hypercholesterolemia. Coupled with the treatment of hypertension and the use of beta-blockers, angiotensin-converting enzyme inhibitors, and aspirin, the potential for reduction of CHD events in patients with known atherosclerosis is significant.
Cholesterol reduction is certainly useful as a CHD risk-reduction strategy and for primary prevention in individuals who are at high risk for CHD and atherosclerosis.
Dietary education about a low-fat (especially saturated fat and trans fat), low-cholesterol diet is of paramount importance.
For patient education resources, see the Cholesterol Center, as well as High Cholesterol, Cholesterol Charts, Lifestyle Cholesterol Management, Cholesterol Lowering Medications, and Statins for Cholesterol.
Hypercholesterolemia is usually discovered during routine screening and does not produce symptoms. Hypercholesterolemia is more common in individuals with a family history of the condition, but lifestyle factors (eg, a diet high in saturated fat) clearly play a major role.
It is important to elicit history about cigarette smoking, diabetes mellitus, and sedentary lifestyle that may contribute to development of hypercholesterolemia and increased cardiovascular risk.
Tendon xanthomas are not present in persons with polygenic hypercholesterolemia. If tendon xanthomas are present, familial hypercholesterolemia or familial defective apoprotein B-100 is the correct diagnosis. Eruptive xanthomas signify extreme hypertriglyceridemia. Xanthelasmas may be present but do not necessarily indicate hypercholesterolemia. Secondary hypercholesterolemia is suggested by stigmata of liver disease, hypothyroidism, hypopituitarism, nephrotic syndrome, and chronic renal disease.
Several drugs and disease states are associated with hypercholesterolemia; however, for the overwhelming majority of patients, the Western lifestyle of a high-fat diet superimposed on a susceptible genotype appears to cause hypercholesterolemia. Nonetheless, ensuring that the patient does not have untreated hypothyroidism, renal disease, or liver disease is important. Furthermore, progestins, anabolic steroids, and glucocorticoids may adversely affect low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) values.
The risk factors for coronary heart disease (CHD), other than LDL-C, in the US National Cholesterol Education Program (NCEP) screening and treatment algorithm are as follows:
Age and sex - Men aged 45 years or older; women aged 55 years or older
Family history of premature CHD (male first-degree relative < 55 y, female first-degree relative < 65 y)
Current cigarette smoking
Hypertension - Blood pressure greater than or equal to 140/90 mm Hg or current antihypertensive drug therapy
Low HDL-C concentration - Less than 40 mg/dL, but one risk factor subtracted if HDL-C concentration is more than 60 mg/dL (This level has been increased from < 35 mg/dL compared with the value from the NCEP Adult Treatment Panel II [NCEP ATP II].)
The US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) suggests screening asymptomatic individuals aged 20 years or older with a fasting lipid panel every 5 years.
Based on US preventive screening taskforce (USPTF) 2014 recommendation, level A recommendations include screening men older than 35 years and women older than 45 years with risk factors. Level B recommendations include screening men aged 20-35 years with risk factors and women aged 20-45 years with risk factors. The risk factors include any one of the following:
Diabetes
Previous personal history of CHD or noncoronary atherosclerosis (eg, abdominal aortic aneurysm, peripheral artery disease, carotid artery stenosis)
Family history of cardiovascular disease in male relatives younger than 50 years or in female relatives younger than age 60 years
Tobacco use
Hypertension
Obesity (BMI ≥30)
Practically speaking, performing a risk factor analysis prior to obtaining screening blood test results is preferable. Patients can have risk factors for coronary heart disease (CHD) other than low-density lipoprotein cholesterol (LDL-C; see Causes). A full lipid profile is obtained after the patient fasts for 9-12 hours. Chylomicrons must be absent and the total triglyceride level must be less than 400 mg/dL in order to use the Friedewald formula to calculate LDL-C. The Friedewald formula is LDL-C = total cholesterol - high-density lipoprotein cholesterol (HDL-C) - triglycerides/5. Direct LDL-C measurements do not offer any greater use, except in patients with marked hypertriglyceridemia. Direct LDL-C measurements can be performed while the patient is in the nonfasting state.
To perform a careful medical evaluation, the practitioner must ascertain all medication intake (both prescription and over-the-counter medications) and perform tests of serum thyroid-stimulating hormone, liver function, creatinine, and urinalysis to rule out secondary dyslipidemias.
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.
The complexity of treatment lies in the numerous guidelines proposed by different organizations. They are outlined briefly below.
ACC/AHA Guidelines 2013
In this guideline, the following four groups of patients were identified who will benefit from statin treatment[16] :
Individuals with clinical atherosclerotic cardiovascular disease (ASCVD), such as acute coronary syndrome, history of MI, stable or unstable angina, coronary revascularization, stroke or TIA presumed to be of atherosclerotic origin, and peripheral arterial disease or revascularization
Individuals with primary elevation of LDL-C of 190 mg/dL or higher, which may include the subgroup of polygenic hypercholesterolemia
Diabetes in persons aged 40-75 years with LDL-C of 70-189 mg/dL
Individuals without clinical ASCVD or diabetes aged 40-75 years with LDL-C of 70-189 mg/dL with an estimated 10-year calculated Framingham risk score of 7.5% or higher
High-intensity statin therapy, which will lower LDL-C by approximately 50%, is recommended for patients with clinical ASCVD, individuals aged 40-75 years with LDL of 190 mg/dL or higher, or those with or without diabetes whose estimated Framingham risk score of CVD risk for 10 years is 7.5% or higher. High-intensity statin therapy includes atorvastatin 80 mg (40 mg if patient unable to tolerate) or rosuvastatin 20 mg. Individuals with polygenic hypercholesterolemia are usually included in this group.
Some suggest that individuals who cannot tolerate high-intensity statins may be switched to moderate-intensity statin therapy, which will lower the LDL-C by 30-50%. The drugs included in this group include atorvastatin 10-20 mg/day, rosuvastatin 5-10 mg/day, simvastatin 20-40 mg/day, pravastatin 40-80 mg/day, lovastatin 40 mg/day, fluvastatin 40 mg bid or fluvastatin XL 80 mg/day, or pitavastatin 2-4 mg/day.
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 (those with acute coronary syndrome, diabetes mellitus, multiple risk factors, uncorrected risk factors such as continued smoking).
Thus, directing statin therapy as per a set goal of LDL-C has not been recommended in these guidelines.
National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines
These 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 http://cvdrisk.nhlbi.nih.gov/calculator.asp).
These guidelines also recommend trying to identify patients with what has been called metabolic syndrome. Such patients in particular should be targeted for therapeutic lifestyle changes. These patients meet at least three 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 or on antihypertensive medications)
Impaired fasting glucose (IFG) value (plasma glucose level ≥110 mg/dL, although the lower limit now generally used in the American Diabetes Association IFG cut point 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 gm 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 as available.
The European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)
The ESC and EAS have recently updated the guidelines for the management of dyslipidemias in 2016. They are available on the ESC site.[17]
ESC have used SCORE (Systemic Coronary Risk Estimation) model to calculate the 10-year risk of a first atherosclerotic event. It takes into consideration age, sex, smoking, systolic blood pressure and total cholesterol. Thus, individuals are placed in subgroups of very high, high, moderate and low risk. Patients with documented CVD, type 1 or type 2 diabetes, very high level of individual risk factors and chronic kidney disease are placed in very high or high risk automatically.
For patients with LDL-C ≥ 190, 100- 154, 70-99 and < 70 mg/dL in low, moderate, high and very high risk respectively, lifestyle intervention and to consider drug if uncontrolled is indicated. Drug therapy is indicated along with lifestyle intervention in patients with high risk and very high risk groups at LDL-C level of 100-154 and 70-99 mg/dL respectively. Statins are considered first line drug in treatment of hypercholesterolemia. However, the choice of statin and its dose depends on the percentage reduction of LDL-C expected in the individual patient.
Contrary to the ACC/AHA guidelines; ESC/EAC do recommend LDL-C lowering goals. It recommends lowering LDL-C as low as possible at least in patients with very high cardiovascular risk.
The following are the goals according to the risk group:
Very high risk: LDL-C < 70 mg/dL or reduction of at least 50% if baseline is between 70-135 mg/dL
High risk: LDL-C < 100 mg/dL or a reduction of at least 50% if the baseline is between 100-200 mg/dL
Low to moderate risk: LDL-C goal is < 115 mg/dL.
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.
Non-HDL-C secondary targets are < 100, 130 and 145 mg/dL respectively for very high, high and moderate risk group patients
HDL-C no target; but >40 mg/dL in men and >48 mg/dL in women indicate lower risk
Triglyceride (TG): No target, but < 150 mg/dL indicate lower risk and higher levels indicate a need to look for other risk factors.
Therapeutic controversies
Post hoc analysis of some studies (eg, Cholesterol and Recurrent Events, West of Scotland Coronary Prevention Study[18] ) have indicated that lowering LDL-C below a reference point will not confer any additional benefit. Similar analyses of other studies (eg, Scandinavian Simvastatin Survival Study,[19, 20] Air Force/Texas Coronary Atherosclerosis Prevention Study[21] ) 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 post-acute 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.[22]
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.[23]
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.
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. Discussion about various such studies is described below.
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. Most patients should be treated with monotherapy, and 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.[19, 20]
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.[20]
An extended follow-up of the Heart Protection Study examined the long-term efficacy and safety of LDL-C-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.[24]
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.
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).[25]
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.
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.[1]
Risk of liver dysfunction and myopathy with statins
Perform liver function testing prior to starting statins or fibrates. Periodic checks of liver function after initiation of statin therapy is not required if no symptoms are present. 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.
Similarly, checking the CK level is only indicated if the patient develops symptoms like muscle aches, pain, tenderness, stiffness, or generalized weakness. The baseline CK level may be checked in individuals who have a higher risk of adverse effects as evidenced by family history of statin intolerance or muscle disease or use of concomitant drugs that may increase the risk 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.
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.
Sometimes, changing the statin is necessary to eliminate the problem. Anecdotal reports suggest that coenzyme Q supplements in patients with muscle aches may reduce myalgias.[26, 27, 28]
Reports suggest that histologic myopathy may occur in the absence of CK elevations. Whether this is a widespread phenomenon is debatable.
Statin intolerance
Statin intolerance creates a treatment dilemma for patients and practitioners in terms of selecting therapeutic options to treat hypercholesterolemia. Recently, ACC have published an expert consensus decision pathway regarding use of non-statin therapy for LDL-C lowering in management of atherosclerotic cardiovascular risk.[29]
The approach to suspected statin intolerance should include temporary discontinuation of statin therapy, lower dosing, re-challenge preferably with 2-3 statins of differing metabolic pathways, and intermittent (1-3x weekly) dosing of long half-life statins.
In selected high-risk patients, such as those with existing ASCVD or LDL-C ≥190 mg/dl, use of non-statins may be considered if maximally tolerated statin therapy has not achieved >50% reduction in LDL-C from baseline.
Ezetimibe is the first non-statin medication that should be considered in most of the patient scenarios, given its safety and tolerability.
Bile acid sequestrants (BAS) may be considered as second-line therapy for patients in whom ezetimibe is not tolerated, but they should be avoided in patients with triglycerides >300 mg/dl.
Alirocumab and evolocumab may be considered if the goals of therapy have not been achieved on maximally tolerated statin and ezetimibe in higher-risk patients with clinical ASCVD or familial hypercholesterolemia.
There are no clear indications of using niacin as additional non statin therapies due to the reported adverse events with its use.
Some of the other therapeutic options are described below.
Red yeast rice is an herbal supplement known to decrease LDL-C levels. It is produced by fermenting white rice with yeast Monascus purpureus. One of the active ingredient is monacolin K- which is the same active chemical ingredient in lovastatin. There have been several trials regarding cholesterol lowering benefit of red yeast rice as well as the use of this supplement in patients who are intolerant to statins due to myalgia.
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.[30] 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.
A small community based randomized control trial in 43 subjects who were not tolerant to statin in the past and randomized to red yeast rice 2400 mg twice daily versus pravastatin 20 mg twice a day by Halbert et al, showed that the incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. Thus in this study, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.[31]
The US FDA has determined that dietary supplements which contain more than minimal amount of monacolin K cannot be sold legally. Also some of the supplements may contain citrinin, which can cause kidney failure and so should be used with caution.[32]
Using other classes of lipid lowering agents, though the actual benefit in lowering CVD risk is controversial.
There are other drugs available to lower LDL cholesterol but are FDA approved only for homozygous hypercholesterolemia:
Mipomersen: Mipomersen is an antisense oligonucleotide inhibitor of mRNA for apolipoprotein B100, the primary apolipoprotein for LDL and VLDL. It is administered by a weekly subcutaneous injection. The FDA has issued a black box warning for hepatotoxicity for mipomersen.[33]
Lomitapide: Lomitapide directly binds and inhibits microsomal triglyceride transfer protein (MTP) in endoplasmic reticulum. This inhibits apo B-containing lipoproteins assembly in enterocytes and hepatocytes, inhibiting the synthesis of chylomicrons and VLDL and thus reduces LDL-C. It is an oral medication and is approved only for use in patients with homozygous hypercholesterolemia. It also carries a risk of hepatotoxicity.[34]
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%.[4] 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).[5]
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.[35]
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.
Obviously, the adoption of a healthier lifestyle that included aerobic exercise and a low-fat diet would probably reduce the prevalence of obesity, hypercholesterolemia, and, ultimately, the risk of coronary heart disease (CHD). Hopefully, younger Americans will adopt these measures to reduce CHD events in the coming years.
Based on ACC/AHA recommendations after the initial lipid panel, repeat the lipid panel 4-12 weeks after initiation of statin therapy and then every 3-12 months based on clinical indication.
The statin (HMG-CoA reductase inhibitor) class of drugs has revolutionized the treatment of hypercholesterolemia. Statins are highly efficacious and very well tolerated.[3] Thus, other drugs are often not needed for low-density lipoprotein cholesterol (LDL-C) reduction. See the charts below on clinical endpoints related to statins.
View Image
Angiographic and clinical endpoint trials with statins.
View Image
Major coronary heart disease (CHD) clinical endpoint studies of primary prevention and stable CHD with statins versus placebo. *not statistically sign....
Newer drugs being studied for control of hypercholesterolemia include PCSK9 (proprotein convertase subtilisin kexin 9) inhibitors, probucol, neomycin, and thyromimetics-eprotirome.
Clinical Context:
Atorvastatin is highly efficacious at high doses, resulting in as much as a 60% reduction in LDL-C. It inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism. The half-lives of atorvastatin and its active metabolites are longer than those of all other statins (ie, approximately 17 h for native drug, approximately 48 h for active metabolites, compared with 3-4 h for other drugs).
Atorvastatin was used for primary prevention (10-mg dose) in the ASCOT trial of subjects with hypertension and at the 80-mg dose in the AVERT, MIRACL, REVERSAL, PROVE-IT, and TNT trials.
Clinical Context:
Fluvastatin is the least potent of statin drugs. The Lescol Intervention Prevention Study showed that in subjects with CHD monitored after a first percutaneous intervention, fluvastatin at 80 mg/d reduced CHD events compared with placebo. It is a synthetically prepared HMG-CoA reductase inhibitor with some similarities to lovastatin, simvastatin, and pravastatin. However, it is structurally distinct and has a different biopharmaceutical profile (eg, no active metabolites, extensive protein binding, minimal CSF penetration). Fluvastatin has been shown to reduce CHD events after revascularization.
Clinical Context:
Lovastatin was the first statin approved by the FDA. It has been shown to retard atherosclerosis in angiographic and carotid ultrasound trials and to reduce clinical events in primary prevention (AFCAPS/TexCAPS). It is a prodrug hydrolyzed in vivo to mevinolinic acid, one of several active metabolites. Once hydrolyzed, it competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, thus reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol can also be taken up by the liver from LDL by endocytosis. The diminishing de novo synthesis of cholesterol leads to increased clearance of circulating LDL. In the AFCAPS/TexCAPS study, 20-40 mg lovastatin daily reduced the incidence of CHD events in a relatively low-risk primary prevention population. Lovastatin is available as IR (Mevacor and generic) and SR (Altocor) dosage forms.
Clinical Context:
Pravastatin reduces CHD events when used in primary prevention in patients with marked LDL-C elevations (WOSCOPS). It also reduces CHD events and mortality rates in patients with CHD and moderate increases in LDL-C (LIPID study). Pravastatin reduces CHD events in patients with cholesterol levels within reference range and known CHD (CARE study), and it reduces cardiovascular events in elderly persons (PROSPER).
Clinical Context:
Simvastatin was the first drug shown to reduce total mortality rate by reducing LDL-C concentrations in patients with CHD with marked LDL-C elevations at baseline (4S). It markedly affects mortality rates and CHD events in patients with CHD and marked hypercholesterolemia (4S). It also reduces CHD events by more than 40% in similar patients with type 2 diabetes mellitus. Simvastatin has also been shown to reduce CHD events in patients with a wide variety of cholesterol concentrations (>135 mg/dL) at baseline, ie, in the HPS. Adverse effects, including LFT abnormalities and myalgia, were minimal at this dose.
Clinical Context:
Rosuvastatin is an HMG-CoA reductase inhibitor that decreases cholesterol synthesis and increases cholesterol metabolism. It reduces total cholesterol, LDL-C, and triglyceride levels and increases the HDL-C level. Rosuvastatin is used adjunctively with diet and exercise to treat hypercholesterolemia. It is the most efficacious of the statins. It may raise HDL-C at higher doses than equally effective doses of atorvastatin. It is not metabolized by the cytochrome P450 system. A dose of 40 mg is associated with hematuria and proteinuria, which is of unknown clinical significance. No clinical outcome studies have been completed as yet.
Clinical Context:
Pitavastatin is an HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.
Studies have shown the efficacy of statin drugs in reducing coronary heart disease (CHD) events, CHD death, and total mortality rates. Efficacy for LDL-C lowering at approved doses of statins is listed in Medical Care. Primary prevention implies the use of statins in an asymptomatic population, which may include some people with clinically occult disease. Secondary prevention implies the use of statins in patients with clinically apparent disease.
The Scandinavian Simvastatin Survival Study (4S) was the first study to show significant reduction (compared with placebo) in the all-cause mortality rate (30%), in CHD events (34%), and in the CHD mortality rate (42%). In addition, subjects with CHD (secondary prevention) who were treated for moderate hypercholesterolemia (eg, treatment with simvastatin, mean dose 27 mg/d) maintained total cholesterol levels of less than or equal to 201 mg/dL for 5.4 years, which was the median follow-up period.
The West of Scotland Coronary Prevention Study (WOSCOPS) studied high-risk male subjects who had no history of CHD events (primary prevention). Pravastatin was administered at a dose of 40 mg/d for 4.9 years. Cardiovascular events were reduced by 31%, and the treatment caused a borderline statistically significant reduction of 31% in the total mortality rate compared with placebo.
The Cholesterol and Recurrent Events (CARE) study of subjects with CHD and cholesterol concentrations within the reference range (mean LDL-C level of 138 mg/dL) examined the effects of pravastatin at a dose of 40 mg/d. Compared with placebo, the CHD events were reduced by 24% at 5 years, with no significant change in total mortality.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) enrolled more than 6000 subjects with average LDL-C concentrations and below-average high-density lipoprotein cholesterol (HDL-C) values. Lovastatin was administered at a dose of 20-40 mg/d for approximately 5 years, resulting in a 37% reduction in first major acute coronary events compared with placebo therapy.
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study used pravastatin at a dose of 40 mg/d for an average of 6.2 years in subjects with CHD; the CHD mortality rate decreased by 24%, and the total mortality rate decreased by 22% compared with placebo treatment.
The Atorvastatin versus Revascularization Treatment (AVERT) Study compared 80 mg atorvastatin daily with standard therapy and angioplasty in subjects with CHD. Although event rates at 18 months were the same between both groups, the time until the first CHD event was longer, with aggressive LDL-C lowering. Angioplasty alone has not been proven to prevent events, so this is not necessarily tantamount to a no-therapy comparison trial.
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial showed borderline significant reduction in coronary events in subjects treated with atorvastatin (80 mg/d) who presented with an acute coronary syndrome, although significant abnormalities revealed via liver function test were common. The major positive finding from this study was a 61% reduction in stroke in the atorvastatin-treated group.
In the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) study that compared pravastatin 40 mg/d versus placebo in subjects aged 70-82 years with a history of CHD or risk factors for CHD, active therapy reduced cardiovascular events by 15%.
The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) assessed the effects of simvastatin (40 mg/d) versus placebo in approximately 20,000 subjects with vascular disease or at high risk for CHD with total cholesterol levels greater than 135 mg/dL, including approximately 6000 subjects with diabetes mellitus. CHD endpoints were reduced by approximately 24% and were effective in multiple subgroups, including subjects with diabetes. The mortality rate was reduced by approximately 15%.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) used 10 mg of atorvastatin versus placebo in approximately 10,000 subjects with hypertension. CHD event rates were reduced approximately 36%. However, most subgroups, including subjects with diabetes mellitus or metabolic syndrome, did not return positive results, perhaps because of the short duration (3.3 y) of the study.
The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared treatment with atorvastatin (80 mg) with treatment with pravastatin (40 mg) in subjects with CHD. After 18 months, the atorvastatin treatment group had a slight decrease in atheroma volume based on intravascular ultrasonography evaluations, and the pravastatin group had a slightly increased atheroma volume.
The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study also compared atorvastatin therapy (80 mg/d) with pravastatin therapy (40 mg/d) in subjects who had been hospitalized for acute coronary syndromes. The baseline LDL-C level was approximately 106 mg/dL. After a mean follow-up of 2 years, the intensively treated group had LDL-C levels of approximately 62 mg/dL, compared with approximately 95 mg/dL in the pravastatin group. Cardiovascular events were reduced by 16%.
Unfortunately, the study had a dropout rate of approximately one third. The number of patients needed to treat was 26, but the number needed to cause transaminase values to exceed 3 times the upper limit of normal was only 46 patients. In this scenario, 26 patients would have to be treated to prevent one clinical event, and 46 patients would have to be treated to see one case of transaminases >3 X ULN (and possibly end up stopping therapy). Interestingly, subjects pretreated with statins or those with baseline LDL-C levels of less than 125 mg/dL did not show a benefit from high-dose atorvastatin therapy compared with pravastatin therapy (40 mg).
A pooled analysis of 5 statin trials revealed that intensive-dose therapy was associated with a greater risk of diabetes when compared with moderate dosing.
The Treating to New Targets (TNT) study assessed the effect of therapy with atorvastatin 80 mg/d versus atorvastatin 10 mg/d in patients with stable CHD for a period of 4.9 years. The mean on-treatment LDL-C level was 77 mg/dL in the former group and 101 mg/dL in the latter group. The relative risk of cardiovascular events was reduced by 22%. Mortality was higher but not significantly statistically different in the high-dose atorvastatin group, although persistent transaminase elevations were 6 times higher in this group.
The statins lower LDL-C by inhibiting HMG-CoA reductase, the enzyme that regulates the rate-limiting step in cholesterol synthesis. The amount of the intermediate (i.e., mevalonate) is lowered, and, subsequently, cholesterol levels are reduced in hepatic cells. This, in turn, results in up-regulation of LDL receptors and increased hepatic uptake of LDL from the circulation.
Clinical Context:
It is FDA approved for the treatment of heterozygous familial and nonfamilial hyperlipidemia, homozygous familial hypercholesterolemia, and homozygous sitosterolemia. It may be administered as monotherapy or in combination with HMG-CoA reductase inhibitors. No clinical endpoint trials have been completed yet. The combination therapy lowers LDL-C levels 45-60%. Its effect on CHD events compared with a statin alone is unknown.
These drugs inhibit dietary cholesterol absorption. Ezetimibe (Zetia) is the only medication in this class with Food and Drug Administration (FDA) approval. It selectively inhibits cholesterol absorption in the intestine by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Alone or with a statin, ezetimibe lowers LDL-C levels by 12-19%. In individuals who hyperabsorb cholesterol, LDL-C reduction of as much as 40% has been documented.
There have been many studies to evaluate the efficacy of Ezetimibe.
The latest study being IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), which was a large randomized controlled trial that included 18,144 patients with acute coronary syndrome who were randomized to receive Vytorin [ezetimibe 10 mg/simvastatin 40 mg] or simvastatin 40 mg and were monitored for up to 9 years. Of patients receiving Vytorin, 32.7% experienced a primary endpoint event (which was death from cardiovascular disease, nonfatal myocardial infarction, unstable angina requiring hospitalization, or coronary revascularization occurring at least 30 days after randomization) compared to 34.7% of the patients receiving 40 mg simvastatin (hazard ratio of 0.936; p value 0.016). No statistical difference in the rate of cardiovascular mortality or rate of death from any other cause was observed between the two groups. There was a reduction in LDL cholesterol by 24% with the use of additional ezetimibe in the regimen. The rate of hemorrhagic stroke was slightly higher in Vytorin group (59%) as compared to simvastatin alone (43%) [hazard ratio 1.38 (0.93-2.04), p value- 0.11]. Also, the study found greater benefit for patients >75 years of age and those with diabetes mellitus, however, the sample size was considered to be small for statistical power significance. Thus, it is considered a landmark study as it is the first clinical trial showing benefit of adding non-statin therapy to statin therapy for cardiovascular benefit.
The ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, was undertaken to demonstrate that progression of atherosclerosis reflected by changes in carotid intima-media thickness (CIMT) would be reduced if ezetimibe was added to 80 mg of simvastatin in patients with heterozygous familial hypercholesterolemia. At the end of the 24-month study, however, no significant difference in CIMT was found between patients using ezetimibe in combination with simvastatin and those using simvastatin alone, despite greater reductions in LDL-C and C-reactive protein levels in the ezetimibe/simvastatin combination group.
Prominent investigators weighed in, stating that if ezetimibe could not improve CIMT, then it had no role in cholesterol management. It should be noted, however, that the cholesterol levels in the study subjects had been aggressively managed for many years, and they did not have increased CIMT at baseline. The study sought to show increased regression and decreased progression in subjects receiving both simvastatin and ezetimibe, compared with simvastatin alone. But regression cannot occur in subjects whose CIMT is normal, and therefore no difference in regression between the 2 treatment groups would have been possible at the end of the study.
In order to demonstrate reduced progression, the CIMT in the simvastatin-only arm would have had to increase. In fact, no progression occurred in this group. Therefore, the simvastatin-ezetimibe subjects could not have benefited from decreased progression because no progression occurred in the simvastatin-only subjects.
The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial, was meant to demonstrate that intensive LDL-C lowering through administration of a daily dose of 40 mg of simvastatin plus 10 mg of ezetimibe would reduce the incidence of major cardiovascular events and also reduce the number of events related to aortic stenosis. As expected, cardiovascular endpoints were clinically and statistically lower in patients using the combination therapy than they were in in placebo-treated patients. However, events related to aortic stenosis were not reduced in the combination group. In addition, the investigators made an unexpected finding, that the incidence of cancer was significantly greater in the ezetimibe/simvastatin group than it was in the patients using placebo (11.1% vs 7.5% [P = 0.01]).
An expert statistician, Richard Peto, with special expertise in analyzing cancer data was invited to analyze the SEAS findings. He was also given access to data from 2 much larger, ongoing clinical trials at that time—SHARP (Study of Heart and Renal Protection) and IMPROVE-IT—with a total of 20,617 randomized patients. SHARP was designed to compare results from the use of simvastatin 20 mg plus ezetimibe to those from placebo, and IMPROVE-IT was designed to compare the results from the administration of simvastatin 40 mg plus ezetimibe to simvastatin 40 mg.
In the combined data from the SHARP and IMPROVE-IT trials, more cancer deaths and fewer cases of cancer were found in the patients assigned to ezetimibe; neither difference was statistically significant. Several features of the data suggested lack of credibility: cancer incidence and death were not prespecified endpoints in SEAS; no excess of cancers at any particular site (more than 15 different sites were involved) were observed; and longer duration of follow-up did not result in an increased trend in cancer incidence or death. The final conclusion by Peto et al was that the available data from the SHARP, IMPROVE-IT, and SEAS trials did not "provide credible evidence of any adverse effect of ezetimibe on rates of cancer." A more definitive answer will be possible when the SHARP and IMPROVE-IT trials are analyzed after a longer follow-up period.
In a study by Zieve et al, the addition of ezetimibe (10 mg) to atorvastatin (10 mg) resulted in significantly more improvement in most serum lipid levels, including better attainment of prespecified LDL-C levels, than did doubling and then quadrupling the atorvastatin dose (to 20mg and then 40 mg), in patients aged 65 years or older with hyperlipidemia and a high risk for coronary heart disease. The study included 1,053 patients; lipid levels were followed over a 12-week period.
Clinical Context:
The immediate-release dosage (IR) form is less hepatotoxic than the sustained-release (SR) form but not as well tolerated by patients because of prostaglandin-mediated flushing, itching, or rash. IR niacin started at low doses and gradually increased over several weeks allows some patients to accommodate to these adverse effects. Higher doses (4-6 g/d) can be used more safely than SR niacin. Niacor and Nicolar are prescription formulations of IR niacin that, while more expensive than over-the-counter brands, may make it less likely that patient will switch brands. Changing the formulation of niacin while on high doses may increase the risk of hepatotoxicity.
The SR dosage form is more hepatotoxic than IR niacin; therefore, strongly advise against switching formulations or brands during treatment. Over-the-counter and prescription SR niacin are available. Over-the-counter brands cost less, but if using this option, recommend only reliable manufacturers. Slo-Niacin is an over-the-counter formulation available in 250-, 500-, and 750-mg tablets. Sundown also is a manufacturer of over-the-counter SR niacin. Prescription SR niacin, Niaspan, is available in 375-, 500-, and 1000-mg tablets.
Niaspan with nocturnal dosing may be more tolerable than the other preparations. Niacin has no real utility in treating pure hypercholesterolemia because of the availability of statins. It is questionable whether adding it to statins to increase a low serum HDL-C reduces CHD risk beyond that observed with a statin alone.
Nicotinic acid/niacin is the most effective agent for raising HDL-C levels. It lowers triglycerides as effectively as fibrates do and is more reliable for lowering LDL-C.
Niacin has several features that make it the most difficult lipid agent to prescribe:
Niacin at doses greater than 2 grams or in time-release formulations can cause significant hepatotoxicity. Immediate-release niacin is the least likely to cause hepatic injury, and time-release niacin is the most likely to cause it. Extended-release niacin has an intermediate risk, and if the FDA maximum approved dose for Niaspan, 2000 mg/day, is not exceeded, the risk of serious hepatic injury is minimal.
Niacin inhibits urate metabolism and can precipitate an acute gouty attack. Patients with a history of gout whose uric acid levels have been normalized with allopurinol have minimal, if any, risk.
Niacin may increase insulin resistance but is not contraindicated in the treatment of patients with diabetes.
Patient tolerability limits niacin's use, the most common side effect being flushing, sometimes accompanied by pruritus and/or rash. Several techniques can lessen or, in some cases, prevent these symptoms, which are prostaglandin-mediated. Time itself will usually decrease symptoms; therefore, to enhance tachyphylaxis and, more importantly, to decrease the risk of hepatotoxicity, niacin should always be started at a low dose and gradually increased ("start low, go slow").
Many patients who will be treated with niacin are already on prophylactic aspirin, 81 mg/day. Aspirin taken 30-60 minutes before niacin may lessen symptoms, but 325 mg is often necessary. Taking niacin with a small, low-fat snack slows absorption and thereby decreases symptoms. Activities that might cause vasodilation (hot food or beverages, spicy food, hot showers) should be avoided. Benadryl is sometimes effective in decreasing a severe reaction.
Niacin is used primarily to treat hypertriglyceridemia, but it also has a beneficial impact on HDL-C and LDL-C levels, and it is the only lipid medication that lowers lipoprotein (a). Niacin has been shown to retard progression of atherosclerosis and reduce CHD events when used in conjunction with a bile acid sequestrant or lovastatin.
The ARBITER 6–HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies) Trial compared the effects of 2 lipid-lowering combination therapies on CIMT. In a prospective, randomized, parallel-group, open-label study, patients received either extended-release niacin (2 g/d target dose) or ezetimibe (10 mg/d) in addition to their long-term statin therapy. All participants (n=363) had been treated with statin monotherapy at a consistent dose. Inclusion required that lipid panels were obtained within 3 months before enrollment showing an LDL cholesterol level of less than 100 mg/dL (2.6 mmol/L), as well as an HDL cholesterol level of less than 50 mg/dL (men) or 55 mg/dL (women) (1.3 or 1.4 mmol/L, respectively). The mean common CIMT change from baseline after 14 months was the study’s primary end point.
Following a prespecified interim analysis conducted after 208 patients (mean age 65 y, 80% men) had completed the trial, the trial was terminated early on the basis of efficacy. The results are described for these 208 patients. In the niacin group, HDL cholesterol level were increased by 18.4% to 50 mg/dL (P <0.001). Niacin also significantly reduced LDL cholesterol and triglyceride levels. The ezetimibe group showed a 19.2% decrease in LDL cholesterol, 66 mg/dL (1.7 mmol/L) (P <0.001). Ezetimibe did not increase HDL cholesterol (HDL levels were actually reduced), but it did reduce triglycerides. Niacin was more effective than ezetimibe in changing mean CIMT over 14 months (P = 0.003), leading to a significant reduction of mean (P = 0.001) and maximal CIMT (P ≤0.001 for all comparisons).
Completed trials with clinical endpoints (eg, AIM-HIGH, ACCORD, and HPS2-THRIVE clinical trials) have shown that the addition of decreased triglycerides and/or increased HDL-C levels in statin-treated patients does not result in further reduction in risk of CV events. Consistent with this conclusion, the FDA has determined that the benefits of niacin ER tablets for coadministration with statins no longer outweighs the risks, and the approval for this indication should be withdrawn. Additionally, the combination products that include simvastatin or lovastatin plus long-acting niacin (ie, Advicor, Simcor) were withdrawn from the US market at the beginning of 2016 and are no longer available.
The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial was aimed to determine whether there is incremental clinical benefit of niacin in reducing cardiovascular events in patients who have attained optimal on-treatment levels of LDL-C with a statin. During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)–lowering therapy did not reduce CV events compared with LDL-C–lowering therapy alone. The study was terminated prematurely due to lack of suggested benefit. Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to aggressive LDL-C–lowering therapy, but a small subgroup of subjects with baseline dyslipidemia showed possible benefit.
HPS2-THRIVE (Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events) was designed to assess the effects of adding extended-release niacin in combination with laropiprant to effective statin-based LDL cholesterol–lowering treatment in 25,673 high-risk patients with prior vascular disease. Laropiprant is an antagonist of the prostaglandin D2 receptor DP1 that has been shown to improve adherence to niacin therapy by reducing flushing in up to two thirds of patients. It did not significantly reduce the risk of major vascular events, either overall or in any particular subgroup of patients. However, the study identified significant hazards, which included new-onset diabetes, increased hospitalization related to diabetes in persons with established diabetes, myopathy, serious bleeding events, and increased rate of infections.
Clinical Context:
Fenofibrate lowers LDL-C better than older fibrate drugs. It is currently used primarily for triglyceride reduction and in mixed dyslipidemias. It induces lipoprotein lipase and decreases hepatic production of apolipoprotein CIII (an inhibitor of LPL) via PPAR alpha activity, which enhances plasma catabolism and clearance of triglyceride-rich particles. Fatty acid oxidation is enhanced by fenofibrate activation of acyl-CoA synthetase and other enzymes. Inhibition of acetyl-CoA carboxylase and fatty acid synthetase activity by fenofibrate further decreases the synthesis of triglycerides. The result is a marked reduction in plasma triglyceride and VLDL levels and an increase in HDL-C levels. The Diabetes Atherosclerosis Intervention Study associated it with decreased progression of coronary atherosclerosis in subjects with type 2 diabetes mellitus.
Clinical Context:
Gemfibrozil is used primarily to lower serum triglyceride levels. Statin clinical endpoint trials have largely made its use for pure cholesterol lowering obsolete. The Veterans Affairs HDL Intervention Trial suggests that gemfibrozil (and probably other fibrates) may be used in patients with CHD, low LDL-C, and low HDL-C. Its mechanism of action is unknown but probably is similar to fenofibrate. It may inhibit lipolysis and secretion of VLDL and decrease hepatic fatty acid uptake.
Older fibrates (eg, clofibrate, gemfibrozil) are used primarily for triglyceride lowering. The Helsinki Heart Study, published in 1987, showed a decrease in CHD events in patients with elevated non–HDL-C concentrations when used in primary prevention. With the advent of statins, fibrates have largely fallen out of favor when pure LDL-C lowering is needed. However, fenofibrate is more efficacious for LDL-C lowering than earlier fibrates. Ongoing studies may help determine if fenofibrate is useful in patients with mixed dyslipidemia, particularly subjects with type 2 diabetes mellitus. The Diabetes Atherosclerosis Intervention Study showed that such subjects with CHD have stabilization of angiographic findings when treated with fenofibrate compared with placebo. This trial was inadequately powered to assess an effect on CHD events. Currently, fenofibrate should probably be relegated to second-line therapy for LDL-C reduction in patients intolerant of statins.
The publication of the Veterans Affairs HDL Intervention Trial is notable. This trial consisted of male subjects with CHD, relatively low LDL-C concentrations (mean of 112 mg/dL), and low HDL-C concentrations (mean of 32 mg/dL). Coronary events were reduced 22% with gemfibrozil treatment compared with placebo treatment. This effect was thought to be due to an increase (6%) in HDL-C levels; however, the almost 30% decrease in triglyceride levels in subjects treated with gemfibrozil may also have played a role in risk reduction.
Clinical Context:
Cholestyramine is FDA approved for the treatment of primary hypercholesterolemia. It is flavored to improve palatability. The light version is sweetened with aspartame and is more palatable to some patients.
Clinical Context:
Colesevelam is a new high-capacity bile acid sequestrant. It is better tolerated than older agents (eg, cholestyramine and colestipol), and drug interactions are less of a problem. It can lower LDL-C levels by 15-18% as monotherapy. It is useful in patients who cannot tolerate statins, have contraindications for statin therapy, or request nonsystemic therapy. It can also be used in combination with a statin for additive LDL-C lowering. Colesevelam has no effect on serum triglyceride levels and a modest beneficial effect on HDL-C. It has also been shown to improve HbA1c in type 2 diabetes patients with diet and exercise. Thus, it may be preferred in this patient population, if intolerant to statins.
These agents are also called resins. Bile acid sequestrants are used primarily as additional therapy in patients with familial hypercholesterolemia who experience inadequate LDL-C lowering with statins. These agents are also useful in pediatric hypercholesterolemia. Several studies show that LDL-C lowering with resins retards the progression of atherosclerosis. The Lipid Research Clinics Coronary Primary Prevention Trial showed that cholestyramine therapy could reduce the risk for CHD events.
Interference with anionic drug absorption and patient compliance are major problems with this class of drugs. They inhibit absorption of many drugs; major ones including statins, estrogen products including OCP, steroids, sulphonylureas, thyroid hormones, multivitamins including Vitamin D, warfarin, diuretics. This should be kept in mind while prescribing these drugs. Resins may be used as an adjunct in primary hypercholesterolemia. These drugs form a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts
Clinical Context:
Evolocumab has been FDA approved for the treatment of heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease and for the treatment of homozygous familial hypercholesterolemia, adjunct to diet and maximally tolerated statin therapy. It is to be administered in adults who require additional lowering of low desnsity lipoprotein cholesterol. It can be given subcutaneously 140 mg every 2 weeks or 420 mg once monthly. Its effects on cardiovascular morbidity and mortality has not been determined.
Clinical Context:
Alirocumab has been FDA approved for the treatment of primary hyperlipidemia, adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low desnsity lipoprotein cholesterol..The initial dose is 75 mg subcutaneous once every two weeks and may increase to 150 mg every two weeks if response is inadequate. The effect of alirocumab on cardiovascular morbidity and mortality has not been established.
Proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors are newly approved lipid lowering agents. They are monoclonal antibodies to PCSK-9 which in vivo act to prevent degradation of LDL receptors (LDL-R). LDL-R are present on the surface of hepatocytes and their main function in uptake of LDL particles and their degradation. The LDL-R again return to the surface of hepatocytes to repeat the process. PCSK 9 binds to LDL-R and promote its degradation.[36] PCSK 9 inhibitors by acting on this pathway can cause dramatic decrease in LDL cholesterol.
In 2003, PCSK 9 mutation was found in 2 families with familial hypercholesterolemia (FH) who did not have the usual FH associated gene mutation.[37] Further research showed that the mechanism of PCSK 9 in increasing LDL cholesterol level and inhibiting PCSK 9 would be a novel mechanism of LDL lowering therapy.[38]
In 2012, Alirocumab was found to lower LDL cholesterol in healthy volunteers as well as patients with familial and non-familial hypercholesterolemia.[36] Subsequently phase 3 trials with both Alirocumab and Evolocumab have shown significant decrease in LDL cholesterol levels.
In the US, two drugs have been approved by the FDA: Alirocumab in July 2015 and Evolocumab in August 2015. Bococizumab is another PCSK 9 inhibitor which is currently in phase 3 trials. Statins increase PCSK 9 levels and thus PCSK 9 inhibitors act synergistically with statins to lower LDL cholesterol levels.[38]
The ODYSSEY COMBO II trial randomly assigned patients at high cardiovascular risk and elevated LDL-C despite maximal doses of statin to alirocumab or ezetimibe with concomitant statin therapy. At week 24, the alirocumab group had 50.6% reduction in LDL-C compared with 20.7% in the ezetimibe group.[39] In the GAUSS-2 trial, patients at high cardiovascular risk who were statin intolerant were randomly assigned to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) or ezetimibe. After 12 weeks, LDL-C lowering in the evolocumab groups ranged between 53% and 56% compared with 37%-39% for ezetimibe.[40] The Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES), was a randomized, double-blind, placebo-controlled, phase 3 trial, which compared evolocumab with placebo in patients with hyperlipidemia who received the study drug for 52 weeks after a run-in period of 4 to 12 weeks of background lipid-lowering therapy showed 57% reduction in LDL cholesterol level.[41] Similar results have been seen in patients with familial hypercholesterolemia.
A meta-analysis of 25 randomized control trials of Evolocumab and Alirocumab with about 12,200 subjects have shown 50% reduction in LDL- cholesterol with favorable increase in HDL cholesterol.[42] Another meta-analysis of 24 randomized controlled trials with 10,159 subjects showed additional significant reduction in all cause mortality as well as secondary end point reduction in myocardial infarction, but not unstable angina.[43] However, most of the trials were of shorter duration and thus long term effect of PCSK 9 inhibitors in cardiovascular mortality need to be ascertained. Two trials are expected to give us more insight into the cardiovascular benefits: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study, a 27,500-patient trial testing evolocumab against statin therapy for the reduction of the primary composite end point of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization (results are expected in late 2017) and The ODYSSEY-Outcomes study which will include 18,000 ACS patients randomized to alirocumab or placebo on top of optimal medical therapy (results expected in early 2018). Studies on PCSK9 Inhibition and the Reduction of vascular Events (SPIRE-1 and SPIRE-2) trial results, using bococizumab will also be available in 2018.
Cost has been a major factor in widespread use of the drug- an estimated $15,000 every year as compared to many generic available statins. However, it is a promising drug in patients with polygenic hypercholesterolemia who require further reduction in LDL cholesterol and are on maximally tolerated statins.
Catherine Anastasopoulou, MD, PhD, FACE, Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Attending Endocrinologist, Department of Medicine, Albert Einstein Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Goral Panchal, MD, Fellow in Endocrinology, Albert Einstein Medical Center
Disclosure: Nothing to disclose.
Parthiv Amin, MD, Fellow in Cardiovascular Medicine, East Tennessee State University, James H Quillen College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Steven R Gambert, MD, Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center
National Health and Nutrition Examination Survey. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/nchs/nhanes.htm. Accessed: 5/19/15.
Carroll MD, Kit BK, Lacher DA, Yoon SSS. Total and high-density lipoprotein cholesterol in adults: National Health and Nutrition Examination Survey, 2011–2012. NCHS Data Brief. 2013;(132):1–8.
National Institutes of Health. Red yeast rice: An introduction. National Center for Complementary and Integrative Health Web site. Available at http://nccam.nih.gov/health/redyeastrice. Accessed: July 13, 2015.
Repatha (evolocumab). Repatha. Available at https://www.repathahcp.com/. 2016; Accessed: September 30, 2016.
Praluent (alirocumab). Praluent. Available at https://www.praluent.com/. 2016; Accessed: September 30, 2016.
Relative risk of coronary heart disease (CHD) mortality versus baseline serum cholesterol over time in 3 large cohorts of young men. CHA is Chicago Heart Association Detection Project in Industry, PG is Chicago Peoples Gas Company, and MRFIT is Multiple Risk Factor Intervention Trial. Adapted from Stamler, 2000.
Simplified diagram of cholesterol metabolism. LDL is low-density lipoprotein, VLDL is very low-density lipoprotein, IDL is intermediate-density lipoprotein, HDL is high-density lipoprotein, and LPL is lipoprotein lipase.
National Health and Nutrition Examination Survey data for hypercholesterolemia among American adults.
Angiographic and clinical endpoint trials with statins.
Major coronary heart disease (CHD) clinical endpoint studies of primary prevention and stable CHD with statins versus placebo. *not statistically significant. + atorvastatin 10 mg is the comparator rather than placebo. ++ LDL-C in the atorvastatin 80 mg group/LDL-C in the atorvastatin 10 mg group.
Relative risk of coronary heart disease (CHD) mortality versus baseline serum cholesterol over time in 3 large cohorts of young men. CHA is Chicago Heart Association Detection Project in Industry, PG is Chicago Peoples Gas Company, and MRFIT is Multiple Risk Factor Intervention Trial. Adapted from Stamler, 2000.
Simplified diagram of cholesterol metabolism. LDL is low-density lipoprotein, VLDL is very low-density lipoprotein, IDL is intermediate-density lipoprotein, HDL is high-density lipoprotein, and LPL is lipoprotein lipase.
National Health and Nutrition Examination Survey data for hypercholesterolemia among American adults.
Angiographic and clinical endpoint trials with statins.
Major coronary heart disease (CHD) clinical endpoint studies of primary prevention and stable CHD with statins versus placebo. *not statistically significant. + atorvastatin 10 mg is the comparator rather than placebo. ++ LDL-C in the atorvastatin 80 mg group/LDL-C in the atorvastatin 10 mg group.
){kind=link}
){kind=link}
){kind=link}
){kind=link}
){kind=link}