ABSTRACT

In evaluating a patient with dyslipidemia the initial step is to decide which particular lipid/lipoprotein abnormalities need to be evaluated and whether they need treatment. These disorders can be divided into elevations of LDL-C, triglycerides, non-HDL-C, and Lp(a) and decreases in plasma HDL-C. Frequently a patient can have multiple lipid/lipoprotein abnormalities. The next step is to rule out secondary causes that could account for the abnormal lipid/lipoprotein levels. These secondary causes can be due to diet, various disease states, or drug therapy. One should be suspicious of a secondary cause if a patient suddenly develops a lipid/lipoprotein abnormality or the lipid/lipoprotein profile suddenly worsens. Next one should consider the possibility of a genetic disorder and therefore ask whether relatives have either premature cardiovascular disease, lipid disorders, or are receiving lipid lowering medications. If the triglyceride levels are markedly elevated one should inquire about a family history of pancreatitis. When the lipid/lipoprotein abnormality is markedly abnormal or begins at a young age, the likelihood of a genetic disorder is increased and the family history assumes even greater importance. In most circumstances a routine lipid panel consisting of plasma triglycerides, total cholesterol, HDL-C, and calculated LDL-C and non-HDL-C provides sufficient information to appropriately decide on who to treat and the best treatment approach. However, it should be recognized that there are certain situations where more sophisticated and detailed laboratory studies can be helpful. The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. Several guidelines have been published that discuss in detail cardiovascular risk assessment and provide recommendations on treatment strategies. Additionally, calculators are available on-line to determine an individual patient’s risk of developing cardiovascular disease in the next 10 years or their lifetime risk. In the prevention of cardiovascular disease, the main priority is to lower the LDL-C levels. Reductions in other apolipoprotein B containing lipoproteins may be instituted if LDL-C levels are at goal. Depending on the specific guideline the percent reduction in LDL-C and/or the goal LDL-C will vary depending upon the patient profile. When LDL-C levels are at goal but triglyceride and non-HDL-C levels are still elevated a recent study suggests further treatment with icosapent ethyl may be beneficial. Whether decreasing Lp(a) is beneficial in preventing cardiovascular disease is uncertain and further studies are in progress. Lifestyle changes are the initial treatment but in most patients’ drug therapy will be necessary. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The initial step is to decide which particular lipid/lipoprotein abnormalities need to be evaluated and whether they need treatment. These disorders can be divided into elevations of LDL-C, triglycerides, non-HDL-C, and Lp(a), and decreases in HDL-C. An increase in non-HDL-C accompanies an increase in LDL-C and/or triglycerides levels. Often a patient can have multiple lipid/lipoprotein abnormalities. For example, it is not uncommon for a patient to have high triglycerides with low HDL-C levels or high LDL-C and high Lp(a) levels.

From a clinical point of view, one is not usually concerned if the LDL-C, Lp(a), or triglyceride levels are low or if the HDL-C level is high. Very low levels of LDL-C and/or triglycerides suggest the presence of other medical issues such as hyperthyroidism, malabsorption, liver disease, chronic infections, cancer, etc. On rare occasions very low LDL-C levels or triglyceride levels can be due to genetic disorders (1). Very high HDL-C levels can also be due to genetic causes (2).

RULE OUT SECONDARY CAUSES

The next step is to rule out secondary causes that could account for the abnormal lipid/lipoprotein levels. These secondary causes can be due to diet, various disease states, or medications. One should be suspicious of a secondary cause if a patient suddenly develops a lipid/lipoprotein abnormality or the lipid/lipoprotein profile suddenly worsens. Patients with genetic abnormalities causing dyslipidemia can have their disorder worsen if they develop secondary causes that further adversely affect lipid/lipoprotein levels.

The key is that if one corrects the secondary cause the lipid/lipoprotein abnormality can often markedly improve or even disappear. For example, hypothyroidism can be accompanied by striking increases in LDL-C levels and the treatment of hypothyroidism can result in a large decrease in LDL-C, often to normal levels (3). Likewise, an improvement in glycemic control in a patient with poorly controlled diabetes may result in a large decrease in serum triglyceride levels (4). Occasionally, the presence of dyslipidemia leads to the discovery of an unrecognized secondary disorder that requires treatment.

Similarly stopping certain drugs can greatly improve the lipid profile (5). For example, in some postmenopausal women with hypertriglyceridemia stopping oral estrogen therapy can result in a marked decrease in triglyceride levels (3). The disorders and drugs that cause lipid/lipoprotein abnormalities are shown in tables 1-7. It should be noted that many disorders and drugs can cause multiple lipid abnormalities. The effects of disorders and drugs in an individual patient can vary depending on genetic background and the presence of other disorders and drugs that effect lipid/lipoprotein levels. For an extensive discussion of the secondary disorders that alter lipid and lipoprotein metabolism please refer to the individual Endotext chapters on these disorders. For additional information on the effect of drugs on lipid and lipoprotein metabolism please see the Endotext chapter on this topic (5).

In a patient with an elevated LDL-C level, one should take a diet history, review the medication list, and check a TSH level to rule out hypothyroidism. Most of the disorders that cause elevations in LDL-C levels, other than hypothyroidism, should be obvious on routine history, physical examination, and laboratory screening. In a patient with an elevated triglyceride level, one should take a diet history and in particular focus on the ingestion of simple sugars and ethanol. One should review the medication list and recognize that many common disease states can adversely impact triglyceride levels including obesity, poorly controlled diabetes, chronic renal failure, HIV, and inflammatory disorders (4,6-9). Weight loss, improvements in glycemic control in patients with diabetes, and a reduction of inflammation can all result in a decrease in triglyceride levels (4,6,7). In a patient with a low HDL-C level one should review the medication list and diet, recognizing that diets very low in fat can result in low HDL-C levels, which are often accompanied by low LDL-C and triglyceride levels (10). In young or very fit males with very low HDL-C levels a careful history directed at anabolic steroid use is essential (3).

THINK ABOUT GENETIC CAUSES

One should always consider the possibility of a genetic disorder and therefore ask whether relatives have either premature cardiovascular disease, lipid disorders, or are taking lipid lowering medications (11). If the triglyceride levels are markedly elevated one should inquire about a family history of pancreatitis. When the lipid/lipoprotein abnormality is markedly abnormal or begins at a young age, the likelihood of a genetic disorder is increased and the family history assumes even greater importance. It is essential to think about the possibility of a genetic disorder because many of the common lipid disorders, such as familial hypercholesterolemia and elevations in Lp(a), have an autosomal codominant genetic transmission and therefore will be present in approximately 50% of family members (12-15). The recognition of the possibility of a genetic disorder will lead to screening family members and if abnormalities are found early treatment can be initiated, which may prevent the adverse consequences of hyperlipidemia. The monogenetic disorders that cause elevations in LDL-C and triglycerides levels and low HDL-C levels are shown in tables 8-11.

Very frequently hypertriglyceridemia and/or hypercholesterolemia are due to polygenic inheritance secondary to combinations of common small effect genes that regulate the production or catabolism of lipoproteins (16). In addition, lifestyle, other disease states, and medications can interact with genetic susceptibilities to result in marked dyslipidemia and therefore even when a genetic disorder is present one should not ignore reversible factors where appropriate treatment can have marked effects on lipid levels. Often secondary factors facilitate the expression of genetic variations to result in an abnormal lipid phenotype. One of the best examples of the interaction of secondary factors and genetic variants is familial dysbetalipoproteinemia (17,18). The apolipoprotein E2/E2 polymorphism occurs in approximately 1% of individuals whereas the clinical disorder only occurs in 1-5/5000 and is frequently associated with other disorders, such as obesity, hypothyroidism, and diabetes, which also perturb lipid metabolism (17,18). A detailed discussion of the genetic disorders that effect plasma lipid and lipoprotein levels can be found in the individual Endotext chapters that focus on these disorders.

ORDERING SPECIAL LABORATORY STUDIES

In most circumstances a routine lipid panel consisting of triglycerides, total cholesterol, HDL-C, and calculated LDL-C and non-HDL-C provides sufficient information to appropriately decide on who to treat and the best treatment approach. In a patient with high fasting triglycerides (>200-400mg/dl) where the LDL-C cannot be accurately calculated measurement of direct LDL-C maybe very helpful. However, it should be recognized that there are certain situations where more sophisticated and detailed laboratory studies can be helpful (19). For example, in a young patient with atherosclerotic vascular disease and no obvious risk factors and a normal lipid profile obtaining specialized lipid/lipoprotein studies including measurement of Lp(a) would be indicated. Indications for measuring Lp(a) are shown in Table 12 (19,20). Note, it is the opinion of some experts that Lp(a) should be measured once in all individuals. The various specialized lipid and lipoprotein studies and their appropriate use are discussed in detail in the Endotext chapter “Utility of Advanced Lipoprotein Testing in Clinical Practice” (19).

DECIDING WHO TO TREAT

The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. A number of guidelines have been published that discuss in detail cardiovascular risk assessment and provide recommendations on treatment strategies (21-24). It should be noted that while these guidelines are similar there are significant differences between their recommendations. Additionally, several calculators are available on-line to determine an individual patient’s risk of developing cardiovascular disease in the next 10 years or their lifetime risk. These issues are discussed in detail in the chapters on Risk Assessment and Guidelines for the Management of High Blood Cholesterol and Triglycerides (25-27). In addition to cardiovascular complications, marked elevations in triglycerides can lead to pancreatitis (26). The National Lipid Association recommends treating triglyceride levels greater than 500mg/dl while the Endocrine Society recommends treating triglycerides if they are greater than 1000mg/dl to lower the risk of pancreatitis (28,29).

GOALS OF THERAPY

The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines do not emphasize specific lipid/lipoprotein goals of therapy but rather to just treat with the statins to lower LDL-C by a certain percentage (21). An exception is that they do recommend in patients with very high-risk ASCVD, to use an LDL-C threshold of 70 mg/dL to consider addition of non-statins to statin therapy. In contrast, other groups, such as the National Lipid Association, International Atherosclerosis Society, European Society of Cardiology/European Atherosclerosis Society, and AACE, do recommend lowering the LDL and non-HDL cholesterol levels to below certain levels depending upon the cardiovascular risk in a particular patient but the recommendations from these organizations are not identical (22,24,29,30).

A detailed discussion of lipid/lipoprotein goals is provided in the chapter on Risk Assessment and Guidelines for the Management of High Blood Cholesterol (25). It should be noted that many lipid experts would recommend trying to achieve an LDL-C levels less than 70mg/dl and non-HDL-C levels less than 100mg/dl in patients with cardiovascular disease or patients at very high risk for the development of cardiovascular disease. In other patients, an LDL-C level less than 100mg/dl and non-HDL-C level less than 130mg/dl is a reasonable goal. AACE and European Society of Cardiology/European Atherosclerosis Society have recommended LDL-C levels less than 55mg/dl in patients at very high risk (22,24). With the results of the IMPROVE-IT trial and PCKS9 inhibitor studies, which showed that adding ezetimibe or a PCSK9 inhibitor to statin therapy resulted in an additional decrease in LDL-C levels and a further reduction in cardiovascular events, the arguments in favor of trying to reach lower lipid/lipoprotein goals has been greatly strengthened (31-33). Moreover, the results of these and other studies provide strong support that the lower the LDL-C level the greater the reduction in cardiovascular events (34,35).

TREATMENT TO REDUCE COMPLICATIONS OF DYSLIPIDEMIA

The first priority in treating lipid disorders is to lower the LDL-C levels to goal, unless triglycerides are markedly elevated (> 500-1000mg/dl), which increases the risk of pancreatitis. LDL-C is the usual first priority because the data linking lowering LDL-C with reducing cardiovascular disease are extremely strong and we now have the ability to markedly decrease LDL-C levels. Dietary therapy is the initial step but in the majority of patients’ dietary modifications will not be sufficient to achieve the LDL-C goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL-C levels but this seldom occurs in clinical practice. Additionally, the dietary changes need to be sustained for a long period of time to be effective and many patients while able to follow an LDL-C lowering diet in the short term are unable to follow the diet for an extended period of time.

Primary Prevention Patients

The first step is determining the risk for developing atherosclerotic cardiovascular disease. There are a number of different calculators for determining risk. In the US the most popular is the ACC/AHA risk calculator (http://www.cvriskcalculator.com/) whereas in Europe the SCORE (Systematic Coronary Risk Estimation) is popular (SCORE2 and SCORE2-OP (escardio.org)). The ACC/AHA recommendations are shown in Figure 1 and the European Society of Cardiology/European Atherosclerosis Society recommendations are shown in Figure 2.

Figure 1.

ACC/AHA Recommendations for Patients without ASCVD, Diabetes, or LDL-C greater than 190mg/dl. Risk enhancers are listed in table 13. (Note the risk is for MI and stroke, both fatal and nonfatal).

Table 13.

ASCVD Risk Enhancers

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Family history of premature ASCVD Persistently elevated LDL > 160mg/dl Chronic kidney disease Metabolic syndrome History of preeclampsia History of premature menopause Inflammatory disease (especially rheumatoid arthritis, psoriasis, HIV) Ethnicity (e.g., South Asian ancestry) Persistently elevated triglycerides > 175mg/dl Hs-CRP > 2mg/L Lp(a) > 50mg/dl or >125nmol/L Apo B > 130mg/dl Ankle-brachial index (ABI) < 0.9

Figure 2.

European Society of Cardiology/European Atherosclerosis Society Recommendations for Primary Prevention Patients. Risk categories are shown in table 14. (Note that the SCORE risk is for a fatal event). There are different tables for different European countries.

Table 14.

Cardiovascular Risk Categories

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Very High Risk	ASCVD DM with target organ damage or at least three major risk factors or early onset of T1DM of long duration (>20 years) Severe CKD (eGFR <30 mL/min/1.73 m2) A calculated SCORE >10% for 10-year risk of fatal CVD FH with ASCVD or with another major risk factor
High Risk	Markedly elevated single risk factors, in particular TC >310 mg/dL, LDL-C >190 mg/dL, or BP >180/110 mmHg Patients with FH without other major risk factors Patients with DM without target organ damage with DM duration >10 years or another additional risk factor Moderate CKD (eGFR 3059 mL/min/1.73 m2). A calculated SCORE >5% and <10% for 10-year risk of fatal CVD
Moderate Risk	Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors Calculated SCORE >1% and <5% for 10-year risk of fatal CVD.
Low Risk	Calculated SCORE <1% for 10-year risk of fatal CVD

A few caveats are worth noting. First, in patients less than 60 years of age it is very helpful to calculate the life-time risk of ASCVD events. Often one will find that the 10-year risk is modest but the life-time risk is high and this information should be included in the risk discussion to help in the decision process. Second, patients should be made aware of the natural history of ASCVD i.e., that it begins early in life and slowly progresses overtime with high LDL-C levels accelerating the rate of development of atherosclerosis and low LDL-C leading to a slower progression of atherosclerosis (35,36). Third, patients should be made aware of genetic studies demonstrating that variants in genes that lead to lifetime decreases in LDL-C levels (for example the HMG-CoA reductase gene, NPC1L1 gene, PCSK9 gene, ATP citrate lyase gene, and LDL receptor gene) result in a decreased risk of cardiovascular events. In a recent study it was reported that a 10mg/dL lifetime decrease in LDL-C with any of these genetic variants was associated with a 16-18% decrease in cardiovascular events whereas a 10mg/dl reduction in LDL-C with lipid lowering therapy results in only approximately a 5% decrease in cardiovascular events (34,37,38). The combination of the natural history and the results observed with genetic variants strongly suggests that early therapy to lower LDL-C levels will have greater effects on reducing the risk of ASCVD events than starting therapy later in life. This information needs to be discussed with the patient. Fourth, if the patient or health care provider are uncertain of the best course of action obtaining a cardiac calcium scan can be very helpful in the decision-making process, particularly in older individuals. A score of 0, particularly in an older patient would indicate that statin therapy is not needed whereas a score > 100 would indicate a need for statin therapy (21). A score of 1-99 favors the use of a statin (21).

In most primary prevention patients, statin therapy is sufficient to lower LDL-C levels to goal (< 100mg/dl). One can usually start with moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg) and increase the statin dose, if necessary, to achieve LDL-C goals. Statins are available as generic drugs and therefore are relatively inexpensive. If a patient does not achieve their LDL-C goal on intensive statin therapy, cannot tolerate statin therapy, or is able to take only a low dose of a statin one can use ezetimibe (generic drug), bempedoic acid, bile acid sequestrants, or PCSK9 inhibitors to further lower LDL-C levels (for detailed discussion of cholesterol lowering drugs see (39)). It should be noted that the addition of ezetimibe or a PCSK9 inhibitor to statin therapy has been shown to reduce cardiovascular events (31-33). In most situations, ezetimibe is the drug of choice given its low cost, ability to reduce ASCVD events, and long-term safety record. If LDL-C is not close to goal PCSK9 inhibitors can be used. Once LDL-C is at goal if the non-HDL-C remains high one can consider the approaches described in the section describing the approach to patients with LDL-C at goal with elevated triglycerides.

CONCLUSION

In summary, modern therapy demands that we aggressively evaluate and when indicated treat lipid disorders to reduce the risk of atherosclerotic cardiovascular disease and in those with very high triglycerides to reduce the risk of pancreatitis.

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