Polygenic Hypercholesterolemia Treatment & Management

Updated: Apr 09, 2021
  • Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD  more...
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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.

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.


Long-Term Monitoring

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.