3146 PART 12 Endocrinology and Metabolism

Familial Combined Hypolipidemia Nonsense mutations in both

alleles of the gene angiopoietin-like 3 (ANGPTL3) lead to low plasma

levels of all three major lipid fractions—TG, LDL-C, and HDL-C—a

phenotype termed familial combined hypolipidemia. ANGPTL3 is a protein synthesized by the liver and secreted into the bloodstream. It inhibits

LPL, thus delaying clearance of TRLs from the blood and increasing TRL

blood concentrations. Deficiency of ANGPTL3, therefore, raises LPL

activity and lowers blood TG; it also lowers LDL-C and raises HDL-C

levels apparently related to the effects of ANGPTL3 on endothelial lipase.

ANGPTL3 deficiency is associated with a reduced risk for CHD. The discovery of this condition led to the development of therapies that antagonize or silence ANGPTL3 to reduce LDL-C and TG levels (see below).

DISORDERS ASSOCIATED WITH REDUCED

HIGH-DENSITY LIPOPROTEINS

Low levels of HDL-C, generally defined as <50 mg/dL in women and

<40 mg/dL in men, are very common in clinical practice. Low HDL-C

is an important independent predictor of increased cardiovascular

risk and has been used regularly in standardized risk calculators. As

an independent risk factor, it has clinical value in the assessment of

cardiovascular risk, and a patient with low HDL-C should generally

be considered at higher risk of ASCVD. However, it is now considered doubtful that low HDL-C is directly causal for the development

of ASCVD. Thus, while HDL-C remains an important biomarker for

assessing cardiovascular risk, it is not considered a particularly attractive target for therapeutic intervention to raise HDL-C levels in order

to reduce cardiovascular risk. HDL-targeted therapies that, remain in

clinical development include a CETP inhibitor and an intravenous

infusion of a lipidated apoA-I particle.

HDL metabolism is strongly influenced by TG metabolism, insulin

resistance, and inflammation, among other environmental and medical

factors. Thus, the HDL-C measurement integrates a number of cardiovascular risk factors, potentially explaining its strong inverse association

with ASCVD. The majority of patients with low HDL-C have some

combination of genetic predisposition and secondary factors. Variants

in hundreds of genes have been shown to influence HDL-C levels.

Even more important quantitatively, obesity and insulin resistance have

strong suppressive effects on HDL-C, and low HDL-C in these conditions is widely observed. Furthermore, the vast majority of patients

with elevated TGs have reduced levels of HDL-C due to the substantial

interplay between the metabolism of TRLs and HDL (see above). Most

patients with low HDL-C who have been studied in detail have accelerated catabolism of HDL and its associated apoA-I protein as the physiologic basis for the low HDL-C. Single-gene Mendelian disorders that

reduce HDL-C activity have been described (Table 407-2) but are rare;

the vast majority of patients with low HDL-C have a polygenic predisposition with secondary factors like obesity, insulin resistance, or HTG.

■ PRIMARY (GENETIC) CAUSES OF LOW HDL-C

Mutations in three key genes encoding proteins that play critical roles

in HDL synthesis and catabolism result in hypoalphalipoproteinemia

(primary low levels of HDL-C). Unlike the genetic forms of hypercholesterolemia, which are invariably associated with premature coronary

atherosclerosis, genetic forms of hypoalphalipoproteinemia are usually

not associated with clearly increased risk of ASCVD. Nevertheless, in

the clinical setting of an HDL-C level <20 mg/dL without accompanying severe HTG, these rare conditions should be considered.

Gene Deletions and Missense Mutations in APOA1 Complete genetic deficiency of apoA-I due to a complete deletion of the

APOA1 gene results in the virtual absence of circulating HDL, proving

the critical role of apoA-I in HDL biogenesis. The APOA1 gene is part

of a gene cluster on chromosome 11 that includes APOA5, APOC3, and

APOA4. Some patients with no apoA-I have large genomic deletions

that include other genes in the cluster. The rare patient lacking apoA-I

can have cholesterol deposits in the cornea and in the skin, and in

contrast to the other genetic disorders of low HDL-C, premature CHD

has been reported. Heterozygotes for apoA-I deletions have reduced

HDL-C levels but no obvious clinical sequelae.

More common, but still rare, are heterozygous missense mutations

in the APOA1 gene associated with low plasma levels of HDL-C. The

first example reported, and still the best known, is an Arg173Cys substitution in apoA-I (so-called apoA-IMilano), found in multiple residents

of a town in northern Italy. Heterozygotes for this mutation have very

low plasma levels of HDL-C (<25 mg/dL) due to impaired LCAT activation and accelerated clearance of the HDL particles containing the

abnormal apoA-I. Despite having very low plasma levels of HDL-C,

these individuals do not appear have an increased risk of premature CHD (neither are they protected against CHD as was initially

believed). Multiple other rare APOA1 missense mutations causing low

HDL-C have been reported. A few of these mutations in APOA1 (as

well as some mutations in APOA2) promote the formation of amyloid

fibrils, causing systemic amyloidosis.

Tangier Disease (ABCA1 Deficiency) Tangier disease is a rare

autosomal co-dominant form of extremely low plasma HDL-C levels

that is caused by mutations in the ABCA1 gene encoding ABCA1, a

cellular transporter that facilitates efflux of unesterified cholesterol

and phospholipids from cells to apoA-I as an acceptor (Fig. 407-3).

Through transporting cellular lipids, ABCA1 in the hepatocytes and

intestinal enterocytes promotes the extracellular lipidation of the

apoA-I secreted from the basolateral membranes of these tissues. In

the genetic absence of ABCA1, the nascent, poorly lipidated apoA-I

is rapidly cleared from the circulation. Thus, patients with Tangier

disease (both ABCA1 alleles mutated) have extremely low circulating

plasma levels of HDL-C (<5 mg/dL) and apoA-I (<5 mg/dL). Cholesterol accumulates in the reticuloendothelial system of these patients,

resulting in hepatosplenomegaly and pathognomonic enlarged, grayish yellow or orange tonsils. An intermittent peripheral neuropathy

(mononeuritis multiplex) or a sphingomyelia-like neurologic disorder

can also be seen in this disorder. Tangier disease may be associated

with some increased risk of ASCVD, although the association is not

as robust as might have been anticipated, given the extremely low

levels of HDL-C in these patients. Patients with Tangier disease also

have low plasma levels of LDL-C, which may attenuate the atherosclerotic risk. Heterozygotes for ABCA1 mutations have moderately

reduced plasma HDL-C levels (~15–40 mg/dL), and the effect on risk

of ASCVD remains uncertain.

Familial LCAT Deficiency This rare autosomal recessive disorder is caused by mutations in LCAT, an enzyme synthesized in the

liver and secreted into the plasma, where it circulates associated with

lipoproteins (Fig. 407-3). As reviewed above, the enzyme is activated

by apoA-I and mediates the esterification of cholesterol to form CEs.

Consequently, in familial LCAT deficiency, the proportion of free cholesterol in circulating lipoproteins is greatly increased (from ~25% to

>70% of total plasma cholesterol). Deficiency in this enzyme interferes

with the maturation of HDL particles and results in rapid catabolism

of circulating apoA-I.

Two genetic forms of familial LCAT deficiency have been described

in humans: complete deficiency (also called classic LCAT deficiency)

and partial deficiency (also called fish eye disease). Progressive corneal

opacification due to the deposition of free cholesterol in the cornea,

very low plasma levels of HDL-C (usually <10 mg/dL), and variable

HTG are characteristic of both disorders. In partial LCAT deficiency,

there are no other known clinical sequelae. In contrast, patients with

complete LCAT deficiency have hemolytic anemia and progressive

renal insufficiency that eventually leads to end-stage renal disease.

Remarkably, despite the extremely low plasma levels of HDL-C and

apoA-I, premature ASCVD is not a consistent feature of either LCAT

deficiency or fish eye disease. The diagnosis can be confirmed in a specialized laboratory by assaying plasma LCAT activity or by sequencing

the LCAT gene.

Primary Hypoalphalipoproteinemia Primary hypoalphalipoproteinemia is defined as a plasma HDL-C level below the tenth percentile in the setting of relatively normal cholesterol and TG levels, no

apparent secondary causes of low plasma HDL-C, and no clinical signs

of LCAT deficiency or Tangier disease. This syndrome is often referred

3147 Disorders of Lipoprotein Metabolism CHAPTER 407

to as isolated low HDL. A family history of low HDL-C suggests an

inherited condition and may trigger an evaluation of one of the Mendelian causes of hypoalphalipoproteinemia. However, most patients with

isolated low HDL do not have an identifiable single-gene disorder and

likely have a polygenic etiology, possibly exacerbated by a secondary

factor. The physiologic defect appears to be accelerated catabolism of

HDL and its apolipoproteins. Several kindreds with primary hypoalphalipoproteinemia and an increased incidence of premature CHD

have been described, although it is not clear if the low HDL-C level is

the cause of the accelerated atherosclerosis in these families.

■ SECONDARY FACTORS THAT

REDUCE HDL-C LEVELS

Hypertriglyceridemia Low HDL-C is very commonly found in

association with elevated TG levels. The lipolysis of TRLs generates

lipids that transfer to HDL, and therefore, any impairment of lipolysis

(the most common cause of elevated TGs) leads to reduced HDL biosynthesis. In settings of elevated TGs, where the HDL-C is not reduced,

alternative explanations (e.g., FDBL, alcohol, estrogens) should be considered. Conversely, an isolated low HDL-C in the presence of normal

TGs should prompt consideration of a primary genetic etiology (as

above) or specific secondary factors (see below).

Very-Low-Fat Diet Dietary fat is positively associated with HDL-C

levels. Individuals who eat very-low-fat vegan diets or who have

anorexia or severe fat malabsorption often have low levels of HDL-C

that are secondary to low dietary fat. In this setting, LDL-C levels are

also usually low as well. There is no known harm to low HDL-C levels

in this setting and no indication for liberalizing the diet solely for the

purpose of raising the HDL-C.

Sedentary Lifestyle and Obesity Physical activity is known to

have a (generally modest) effect in raising HDL-C levels, and conversely, a sedentary lifestyle is often associated with low HDL-C levels.

Concordant with that observation, obesity is frequently associated with

low HDL-C levels even when overt insulin resistance or HTG is not

present. Increased physical activity and weight loss usually have some

effect in raising HDL-C, which is not the primary reason for recommending these interventions but can have a motivating influence on

the patient.

ANABOLIC STEROIDS AND TESTOSTERONE Anabolic steroids have

a well-established effect on lowering HDL-C levels, sometimes quite

dramatically. Testosterone supplementation can also reduce HDL-C

levels, although not to the degree caused by anabolic steroids. In a

young male patient who presents with unexplained very low HDL-C,

a careful history of medication and supplement use should be taken.

APPROACH TO THE PATIENT

Lipoprotein Disorders

The major goals in the diagnosis and clinical management of lipoprotein disorders are (1) prevention of acute pancreatitis in patients

with severe HTG and (2) prevention of CVD and related cardiovascular events. Given the high prevalence of dyslipidemia and the

proven clinical benefits of early diagnosis and initiation of therapy,

it is essential that physicians screen lipids systematically, rule out

secondary causes of dyslipidemia, suspect inherited disorders of

lipoprotein metabolism where appropriate, actively promote family-based cascade screening, carefully assess risk for ASCVD and

consider additional risk stratification approaches, and be knowledgeable about the wide range of existing therapeutic options for

dyslipidemia. The field of clinical lipidology has matured and is

moving toward a more systematic clinical application of genomic

medicine. Diagnostic DNA sequencing or genotyping in patients

with suspected FCS, FPLD, FH, and FDBL has the potential to

enhance molecular diagnosis, facilitate appropriate therapeutic

interventions, and promote family-based cascade screening.

DIAGNOSIS

A critical first step in managing a lipoprotein disorder is to attempt

to determine the class or classes of lipoproteins that are increased

or decreased in the patient. Once the dyslipidemia is accurately

classified, efforts should be directed to identify or rule out any possible secondary causes (Table 407-3). A careful social, medical, and

family history should be obtained. In patients with elevated TG levels (>150 mg/dL), a fasting glucose and/or hemoglobin A1c should

be obtained to rule out diabetes. In patients with elevated LDL-C

levels (>160 mg/dL), a TSH should be obtained to rule out hypothyroidism and consideration should be given to the possibility of

liver or kidney disease. Once secondary causes have been ruled

out, attempts should be made to diagnose a primary lipid disorder,

because the underlying genetic defect can provide important prognostic information regarding the risk of pancreatitis in severe HTG

and the risk of ASCVD in other dyslipidemias, as well as impact

on the choice of drug therapy and the screening of other family

members. Obtaining the correct diagnosis often requires a detailed

family history, lipid analyses in family members, and sometimes

specialized or genetic testing.

Severe Hypertriglyceridemia If the fasting plasma TG level is

>500 mg/dL, the patient has severe HTG and may be at risk for

pancreatitis. If the TG levels are persistently severely elevated,

especially if they are >1000 mg/dL, and the total cholesterol-to-TG

ratio is >8, FCS should be considered, and genetic testing of an FCS

gene panel may be indicated (Table 407-2). If central obesity, insulin

resistance, and/or fatty liver disease are also present, consideration

should be given to the possibility of FPLD, and an FPLD gene panel

may be indicated (Table 407-2). However, most individuals with

severe HTG do not have a single-gene disorder but have increased

polygenic risk for high TGs often exacerbated by secondary factors (diet, alcohol, obesity, insulin resistance, medications). Such

patients are still at risk for acute pancreatitis and should be treated

to reduce their TG levels and thus their risk of pancreatitis (see

below).

Hypercholesterolemia If the LDL-C levels are >190 mg/dL, the

patient has severe hypercholesterolemia and is at risk for premature

ASCVD. In absence of secondary causes, FH should be considered,

particularly if there is a family history of hypercholesterolemia

and/or premature CHD, and genetic testing of an FH gene panel

may be indicated (Table 407-2). While FH is a clinical diagnosis,

a finding of a causal mutation may appropriately result in earlier

and more aggressive therapy to lower LDL-C and should also

promote family-based cascade screening as per the Centers for

Disease Control and Prevention guidelines labeling FH as a Tier 1

condition. Recessive forms of severe hypercholesterolemia are rare,

but if a patient with severe hypercholesterolemia has parents with

normal cholesterol levels, ARH, sitosterolemia, and LALD should

be considered, and genetic testing may be indicated (Table 407-2).

Patients without an identified genetic variant or who have more

moderate hypercholesterolemia are likely to have polygenic hypercholesterolemia but should still be considered at risk and eligible for

treatment (see below).

Mixed Hyperlipidemia Elevations in fasting plasma levels of both

TGs (>150 mg/dL) and LDL-C (>130 mg/dL), often accompanied

by reduced levels of HDL-C (<40 mg/dL in men and <50 mg/dL in

women), are common, and such patients are often diagnosed as having “mixed hyperlipidemia.” Most such patients are at increased risk

of ASCVD and merit consideration of lifestyle and/or pharmacologic interventions. Secondary factors, particularly obesity, insulin

resistance, and type 2 diabetes, are common in such patients, who

often also have increased polygenic risk for dyslipidemia. The presence of palmar or tuberous xanthomas or an unusual lipid profile

of total cholesterol and TG levels in the same range with an HDL-C

that is not reduced should prompt consideration of FDBL, or type

III hyperlipidemia, and can be diagnosed by a nuclear magnetic

3148 PART 12 Endocrinology and Metabolism

resonance (NMR) lipoprotein profile or genetic testing for the

APOE2 genotype. FDBL patients should be managed aggressively

due to substantially increased risk of ASCVD. More commonly,

patients with mixed hyperlipidemia, particularly those with family

histories of dyslipidemia or premature ASCVD, have familial combined hyperlipidemia (FCHL). ApoB should be measured in such

patients, and the finding of substantially elevated apoB levels can

help identify patients with FCHL, who are at especially increased

risk of ASCVD and require more aggressive treatment.

TREATMENT

Severe Hypertriglyceridemia

There is a well-established observational relationship between

severe HTG, particularly chylomicronemia, and acute pancreatitis;

however, there has never been a clinical trial designed or powered to

definitively prove that intervention to reduce TGs reduces the risk

of pancreatitis. Nevertheless, it is generally considered appropriate

medical practice to intervene in patients with TGs >500 mg/dL in

order to reduce the risk of pancreatitis. It remains uncertain whether

chylomicronemia increases risk for ASCVD per se. Importantly,

moderate HTG (TG 150–500 mg/dL) is associated with increased

ASCVD risk; management of these patients is focused on reducing

risk of ASCVD and on reducing LDL-C, non-HDL-C, and apoB.

LIFESTYLE AND MODIFIABLE FACTORS

In patients with severe HTG, lifestyle modification can be associated

with a significant reduction in plasma TG level. Patients who drink

alcohol should be encouraged to decrease or preferably eliminate

their intake. Patients with severe HTG often benefit from a formal

dietary consultation with a dietician intimately familiar with counseling patients on the dietary management of high TGs. Dietary fat

intake should be restricted to reduce the formation of chylomicrons

in the intestine. The excessive intake of simple carbohydrates should

be discouraged because insulin drives TG production in the liver.

Aerobic exercise and even increase in regular physical activity can

have a positive effect in reducing TG levels and should be strongly

encouraged. For patients who are overweight, weight loss can help

to reduce TG levels. In extreme cases, bariatric surgery has been

shown to not only produce effective weight loss but also substantially reduce plasma TG levels. Many patients with diabetes have

HTG, and better control of diabetes can result in lowering of TGs.

Finally, certain medications can exacerbate HTG (Table 407-3).

PHARMACOLOGIC THERAPY

Despite lifestyle interventions, many patients with severe HTG

require pharmacologic therapy (Table 407-4). Patients who persist

in having fasting TG >500 mg/dL despite active lifestyle management are candidates for pharmacologic therapy. The two major

classes of drugs used for management of these patients are fibrates

and omega-3 fatty acids (fish oils). In addition, statins can reduce

plasma TG levels and also reduce ASCVD risk and should be used

in patients with severe HTG who are at increased risk of ASCVD.

Fibrates Fibric acid derivatives, or fibrates, are agonists of PPARα,

a nuclear receptor involved in the regulation of lipid metabolism.

Fibrates stimulate LPL activity (enhancing TG hydrolysis), reduce

apoC-III synthesis (enhancing lipoprotein remnant clearance),

promote β-oxidation of fatty acids, and may reduce VLDL TG

production. Fibrates reduce TG levels by ~30% in individuals

with severe HTG and are often used as first-line therapy. They

sometimes modestly raise LDL-C levels. Fibrates are generally well

tolerated but can cause myopathy, especially when combined with

statins, can raise creatinine, and are associated with an increase in

gallstones. Fibrates can potentiate the effect of warfarin and certain

oral hypoglycemic agents.

Omega-3 Fatty Acids (Fish Oils) Omega-3 fatty acids, or omega-3

polyunsaturated fatty acids (n-3 PUFAs), commonly known as fish

oils, are present in high concentration in fish and in flaxseed. The

n-3 PUFAs used for the treatment of HTG are eicosapentaenoic

acid (EPA) and docosahexaenoic acid (DHA). n-3 PUFAs have been

concentrated into capsules and in doses of 3–4 g/d are effective at

lowering fasting TG levels by ~30%. Fish oils can cause an increase

in plasma LDL-C levels in some patients. Icosapent ethyl is an EPAonly product that has been shown to reduce cardiovascular events

in patients with HTG. In general, fish oils are well tolerated, with

the major side effect being dyspepsia. They appear to be safe, at least

at doses up to 3–4 g, but can be associated with a prolongation in the

bleeding time. Fish oils can be first-line therapy for the treatment of

severe HTG or can be used in combination with fibrates.

APOC3 Silencing ApoC-III inhibits LPL and TRL uptake, and

genetic variants in the APOC3 gene reduce TG levels and risk of

ASCVD. Volanesorsen is an antisense oligonucleotide targeted

to the APOC3 mRNA in the liver; it significantly reduces plasma

apoC-III and TG levels and is approved in Europe for patients with

FCS. It has been associated with severe thrombocytopenia. Additional therapeutic approaches to APOC3 and other targets for TG

lowering are in development.

Hypercholesterolemia (Elevated LDL-C

with or without Elevated TG)

There are abundant and compelling data that intervention to

reduce LDL-C substantially reduces the risk of ASCVD, including

myocardial infarction and stroke, as well as total mortality. Thus, it

is imperative that patients with hypercholesterolemia be carefully

assessed for cardiovascular risk and need for intervention. It is also

worth emphasizing that patients with or at high risk for ASCVD

who have plasma LDL-C levels in the “normal” or average range

also benefit from intervention to reduce LDL-C levels.

LIFESTYLE AND MODIFIABLE FACTORS

In patients with elevated LDL-C, lifestyle modifications can be

effective but are often less effective than in HTG. Patients should

receive dietary counseling to reduce the content of saturated fats

and trans fats in the diet. Obese patients should make an effort to

lose weight. Regular aerobic exercise has relatively little impact on

reducing plasma LDL-C levels, although it has cardiovascular benefits independent of LDL-C lowering. Patients with hypothyroidism

should be optimally controlled. Finally, certain medications can

elevate LDL-C levels (Table 407-3).

PHARMACOLOGIC THERAPY

The decision to use LDL-lowering drug therapy (Table 407-4)—

with a statin being first-line therapy—depends on the presence

of ASCVD or, if absent, the level of LDL-C as well as the level of

cardiovascular risk. In patients with established ASCVD, drug

therapy to reduce LDL-C is well supported by clinical trial data to

reduce LDL-C as long as it remains >70 mg/dL, using combination

drug therapy if necessary. In the absence of ASCVD, patients with

FH must be treated to reduce the very high lifetime risk of ASCVD,

and treatment should be initiated as early as possible, ideally during

childhood. Otherwise, the decision to initiate LDL-lowering drug

therapy is generally determined by the level of cardiovascular risk.

For patients >40 years old without clinical CVD, the AHA/ACC

risk calculator can be used to determine the 10-year absolute risk

for CVD, and current guidelines suggest that a 10-year risk >7.5%

merits consideration of statin therapy regardless of plasma LDL-C

level. For younger patients, the assessment of lifetime risk of CVD

may help inform the decision to start a statin, as well as a careful

assessment of family history of ASCVD. In patients for whom the

decision to start a statin is uncertain due to borderline ASCVD

risk and/or borderline LDL-C levels, additional risk stratification

might be considered. Blood tests that predict ASCVD risk beyond

3149 Disorders of Lipoprotein Metabolism CHAPTER 407

traditional risk factors include apoB, Lp(a), and high-sensitivity

C-reactive protein (hs-CRP). In patients who are of a sufficient age

(men >40 years and women >50 years), a coronary artery calcium

(CAC) score has been shown to provide independent information

about risk of CAD. Elevated levels of one or more of these biomarkers or an elevated CAC score might be used to justify initiation

of statin therapy in primary prevention for patients who are in a

borderline zone with regard to treatment. Finally, given the strong

polygenic contribution to ASCVD, there is increasing interest in

the concept that a polygenic risk score for CAD might eventually

be of clinical utility in lifetime risk assessment and decision-making

regarding statin therapy in primary prevention.

HMG-CoA Reductase Inhibitors (Statins) Statins inhibit HMGCoA reductase, a key enzyme in cholesterol biosynthesis. By

inhibiting cholesterol synthesis in the liver, statins lead to a counterregulatory increase in the expression of the LDL receptor and thus

accelerated clearance of circulating LDL, resulting in a dose-dependent

reduction in plasma levels of LDL-C. The magnitude of LDL-C

lowering associated with statin treatment (~30–55%) varies by

statin and among individuals, but once a patient is on a statin, the

doubling of the statin dose produces a ~6% further reduction in the

level of plasma LDL-C. An extensive body of randomized clinical

trials has clearly established that statin therapy significantly reduces

major cardiovascular events (and in some cases total mortality) in

both primary and secondary prevention settings. The seven statins

currently available differ in their LDL-C–reducing potency

(Table 407-4). Current recommendations are to use high-intensity

statin therapy in patients with ASCVD or deemed at high risk of

ASCVD. Statins also reduce plasma TGs in a dose-dependent fashion, which is roughly proportional to their LDL-C–lowering effects.

Statins, taken in tablet form once a day, are remarkably safe

and well tolerated. The most important side effect associated

with statin therapy is muscle pain, or myalgia, which occurs in

3–5% of patients, some of whom are unable to tolerate any statin.

Severe myopathy (associated with an increase in plasma creatine

kinase [CK]) and even rhabdomyolysis can occur rarely with statin

treatment. The risk of statin-associated myalgia or myopathy is

increased by the presence of older age, frailty, renal insufficiency,

and coadministration of drugs that interfere with the metabolism

of statins, such as erythromycin and related antibiotics, antifungal agents, immunosuppressive drugs, and fibric acid derivatives

(particularly gemfibrozil). In the event of muscle symptoms, a

plasma CK level may be obtained to differentiate myopathy from

myalgia. Serum CK levels need not be monitored on a routine basis

in patients taking statins because an elevated CK in the absence of

symptoms does not predict the development of myopathy and does

not necessarily suggest the need for discontinuing the drug. Statins

can result in elevation in liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), but it is usually

mild and transient and generally does not require discontinuation.

Finally, meta-analyses of large randomized controlled clinical trials

with statins indicate a slight excess in incident type 2 diabetes, an

observation as yet not fully understood. However, the cardiovascular benefits associated with statin therapy far outweigh the slight

increase in incident diabetes. Based on their safety and extensively

documented benefit with regard to cardiovascular outcomes, statins

are the clear drug class of choice for LDL-C reduction and are by far

the most widely used class of lipid-lowering drugs.

Cholesterol Absorption Inhibitor Cholesterol within the lumen of

the small intestine is derived from the diet (about one-third) and

the bile (about two-thirds) and is actively absorbed by the enterocyte through a process that involves the protein NPC1L1. Ezetimibe (Table 407-4) is a cholesterol absorption inhibitor that binds

directly to and inhibits NPC1L1 and blocks the intestinal absorption of cholesterol. Ezetimibe (10 mg taken once daily) inhibits

cholesterol absorption by almost 60%, resulting in a reduction in

delivery of dietary sterols in the liver and a compensatory increase

in hepatic LDL receptor expression. The mean reduction in plasma

LDL-C on ezetimibe (10 mg) is 18%, and the effect is additive when

used in combination with a statin. Effects on TG and HDL-C levels

are negligible. Ezetimibe added to a statin has been shown to significantly reduce major cardiovascular events compared with statin

alone. It is generally considered the second-line option for adding

to a statin in order to achieve further LDL-C reduction. Ezetimibe

is very safe and well-tolerated. When used in combination with

a statin, monitoring of liver transaminases is recommended. The

only roles for ezetimibe in monotherapy are in patients who do not

tolerate statins and in some patients with sitosterolemia.

PCSK9 Inhibitors Circulating PCSK9 targets the LDL receptor for

lysosomal degradation, thus reducing its recycling and abundance

at the surface of the hepatocyte. Genetic loss of function of PCSK9

results in low levels of LDL-C and protection from CAD. Antibodies to PCSK9 (Table 407-4) sequester it and functionally increase

the number of LDL receptors available to remove LDL from the

blood. They are highly effective in lowering LDL-C, with an ~60%

reduction in LDL-C. They also reduce plasma levels of Lp(a)

modestly. Both PCSK9 antibodies have been shown to significantly

reduce cardiovascular events when added to a statin in patients with

existing CAD. These antibodies are administered subcutaneously

every 2 weeks. They are generally well tolerated, with the major side

effect being injection site reactions. They are generally indicated

as second-line (added to statin) or third-line (added to statin plus

ezetimibe) therapy in patients with FH or ASCVD in whom LDL-C

is not reduced to acceptable levels with a statin (with or without

ezetimibe) alone. An alternative approach to silencing PCSK9,

inclisiran, is a therapeutic siRNA molecule that targets the PCSK9

mRNA in the liver. In contrast to the antibodies, it is administered

subcutaneously every 6 months. It is effective in reducing LDL-C

by ~60% and appears to be well tolerated and safe; a cardiovascular

outcomes trial is ongoing.

ATP Citrate Lyase Inhibitor Bempedoic acid is a first-in-class

competitive inhibitor of ATP citrate lyase (ACL), which acts on

mitochondrial-derived citrate to generate production of acetylCoA, which is subsequently used for cholesterol synthesis. Thus, it

reduces cholesterol synthesis through a different mechanism than

statins, ultimately upregulating the hepatic LDL receptor. In phase

3 trials, bempedoic acid 180 mg daily reduced LDL-C by ~18%

when added to a statin and by ~23% as monotherapy. A cardiovascular outcomes trial is ongoing. Bempedoic acid is a prodrug

that requires activation by very-long-chain acyl-CoA synthetase-1

(ASCVL1), which is not expressed in skeletal muscle, potentially

explaining why it has less association with myalgias than statins;

indeed, it has been shown to be relatively well tolerated in patients

with statin intolerance. It is available in a fixed-dose combination

with ezetimibe, which reduced LDL-C by ~36%, for patients who

are statin intolerant. It can be used in combination with statins but

should not be used with simvastatin in a dose >20 mg. Bempedoic

acid is associated with increased uric acid levels and incidence of

gout; it was also associated with increased incidence of tendon

rupture in phase 3 trials. Unlike statins, it was not associated with

increased incidence of diabetes.

Bile Acid Sequestrants (Resins) Bile acid sequestrants (BAS)

bind bile acids in the intestine and promote their excretion rather

than reabsorption in the ileum. To maintain the bile acid pool size,

the liver diverts cholesterol to bile acid synthesis. The decreased

hepatic intracellular cholesterol content results in upregulation of

the LDL receptor and enhanced LDL clearance from the plasma.

BAS, including cholestyramine, colestipol, and colesevelam (Table

407-4), primarily reduce plasma LDL-C levels but can cause an

increase in plasma TGs. Therefore, patients with HTG generally

should not be treated with bile acid–binding resins. Cholestyramine

and colestipol are insoluble resins that must be suspended in liquids.

Colesevelam is available as tablets but generally requires up to six to

seven tablets per day for effective LDL-C lowering. BAS are effective

3150 PART 12 Endocrinology and Metabolism

in combination with statins and in combination with ezetimibe.

Side effects of resins are limited to the gastrointestinal tract and

include bloating and constipation. Because BAS are not systemically

absorbed, they are very safe and are the cholesterol-lowering drug

of choice in children and in women who are pregnant, lactating, or

actively trying to conceive. However, they are otherwise fourth- or

fifth-line drugs for LDL-C reduction in other settings.

Specialized Drugs for HoFH Three “orphan” drugs are approved

specifically for the management of HoFH, a rare condition caused

by biallelic mutations in the major genes causing FH in which

patients respond poorly to traditional LDL-lowering medications.

Lomitapide is a small-molecule inhibitor of MTP that reduces

LDL-C by ~50%, and mipomersen is an antisense oligonucleotide

against apoB tgat reduces LDL-C by ~25%. Both of these drugs

reduce hepatic VLDL production and thus LDL-C levels; however,

due to their mechanism of action, each drug causes an increase in

hepatic fat, the long-term consequences of which are unknown.

In addition, lomitapide is associated with gastrointestinal-related

side effects, and mipomersen is associated with skin reactions and

flulike symptoms. Finally, an antibody inhibitor of ANGPTL3,

evinacumab, was approved in 2021 for the treatment of HoFH. In a

phase 3 trial, an intravenous infusion every 4 weeks reduced LDL-C

levels in patients with HoFH by ~50% and was well tolerated. One

of these three drugs should be considered in HoFH patients after

a trial of a high-intensity statin, and possibly a PCSK9 inhibitor, is

shown to be insufficient to reduce LDL-C levels.

LDL Apheresis Patients with severe hypercholesterolemia who

cannot reduce their LDL-C to acceptable levels despite optimally

tolerated combination drug therapy are candidates for LDL apheresis. In this process, the patient’s plasma is passed over a column

that selectively removes the LDL, and the LDL-depleted plasma is

returned to the patient. LDL apheresis is indicated for patients on

maximally tolerated combination drug therapy (including a PCSK9

inhibitor) who have CHD and a plasma LDL-C level >200 mg/dL

or no CHD and a plasma LDL-C level >300 mg/dL; LDL apheresis

could be considered in high-risk patients who have an LDL-C >160

mg/dL on maximal therapy.

■ FURTHER READING

Baass A et al: Familial chylomicronemia syndrome: An under-recognized

cause of severe hypertriglyceridaemia. J Intern Med 287:340, 2020.

Brown EE et al: Genetic testing in dyslipidemia: A scientific statement

from the National Lipid Association. J Clin Lipidol 14:398, 2020.

Feingold KR: Approach to the patient with dyslipidemia. In Endotext.

Available at https://www.ncbi.nlm.nih.gov/books/NBK326736/. Last

updated May 11, 2020.

Hussain I et al: Lipodystrophies, dyslipidaemias and atherosclerotic

cardiovascular disease. Pathology 51:202, 2019.

Li F, Zhang H: Lysosomal acid lipase in lipid metabolism and beyond.

Arterioscler Thromb Vasc Biol 39:850, 2019.

Luirink IK et al: 20-Year follow-up of statins in children with familial

hypercholesterolemia. N Engl J Med 381:1547, 2019.

Schmidt AF et al: PCSK9 monoclonal antibodies for the primary and

secondary prevention of cardiovascular disease. Cochrane Database

Syst Rev 10:CD011748, 2020.

Sniderman AD et al: Apolipoprotein B particles and cardiovascular

disease: A narrative review. JAMA Cardiol 4:1287, 2019.

Sturm AC et al: Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. J Am Coll Cardiol 72:662, 2019.

Trinder M et al: Association of monogenic vs polygenic hypercholesterolemia with risk of atherosclerotic cardiovascular disease. JAMA

Cardiol 5:390, 2020.

The metabolic syndrome (syndrome X, insulin resistance syndrome)

consists of a constellation of metabolic abnormalities that confer

increased risk of cardiovascular disease (CVD) and diabetes mellitus.

Evolution of the criteria for the metabolic syndrome since the original

definition by the World Health Organization in 1998 reflects growing

clinical evidence and analysis by a variety of consensus conferences

and professional organizations. The major features of the metabolic

syndrome include central obesity, hypertriglyceridemia, low levels of

high-density lipoprotein (HDL) cholesterol, hyperglycemia, and hypertension (Table 408-1).

■ GLOBAL HEALTH/EPIDEMIOLOGY

The most challenging feature of the metabolic syndrome to define is

waist circumference. Intraabdominal circumference (visceral adipose

tissue) is most strongly related to insulin resistance and risk of diabetes

and CVD, and for any given waist circumference, the distribution of

adipose tissue between subcutaneous (SC) and visceral depots varies

substantially. Thus, within and between populations, there is a lesser

versus greater risk at the same waist circumference. These differences

in populations reflect the range of waist circumferences considered to

confer risk in different geographic locations (Table 408-1).

The prevalence of the metabolic syndrome varies around the world,

in part reflecting the age and ethnicity of the populations studied and

the diagnostic criteria applied. In general, the prevalence of the metabolic syndrome increases with age. The prevalence of metabolic syndrome in the U.S. adult population meeting the criteria of the National

Cholesterol Education Program (NCEP) and Adult Treatment Panel

III (ATPIII) is ~35%. Greater global industrialization is associated

with rising rates of obesity and expected increase in the prevalence of

the metabolic syndrome, especially as the population ages. Moreover,

the rising prevalence and severity of obesity among children reflect

features of the metabolic syndrome in a younger population, now

estimated to be 12 and 30% among obese and overweight children,

respectively.

Using National Health and Nutrition Examination Survey

(NHANES) data from 2012–2016, the prevalence of metabolic syndrome in the United States was 34.7% and not different between

men (35.1%) and women (34.3%). The highest prevalence was in

“other” race/ethnicity (39.0%) followed by Hispanic (36.3%) and nonHispanic white (36.0%). Although increased from 32.5% in 2010–2012,

the increase was not significant; however, the prevalence did increase

significantly among those aged 20–39 years (from 16.2 to 21.3%) and

in women (from 31.7 to 36.6%), Asian participants (from 19.9 to

26.2%), and Hispanic participants (from 32.9 to 40.4%). As in previous

data, prevalence of metabolic syndrome increased with increasing age

among all subgroups, i.e., from 19.5% among those aged 20–39 years

to 48.6% among those aged ≥60 years.

The frequency distribution of the five components of the syndrome

for the U.S. population (NHANES III) is summarized in Fig. 408-1.

Increases in waist circumference predominate among women, whereas

increases in fasting plasma triglyceride levels (i.e., >150 mg/dL), reductions in HDL cholesterol levels, and hyperglycemia are more likely in

men.

■ RISK FACTORS

Overweight/Obesity The metabolic syndrome was first described

in the early twentieth century; however, the worldwide overweight/

obesity epidemic has recently been the force driving its increasing

recognition. Central adiposity is a key feature of the syndrome, and

the syndrome’s prevalence reflects the strong relationship between

waist circumference and increasing adiposity. However, despite the

importance of obesity, patients who are of normal weight may also be

408 The Metabolic Syndrome

Robert H. Eckel

3151The Metabolic Syndrome CHAPTER 408

insulin-resistant and may have the metabolic syndrome. This phenotype is particularly evident for populations in India, Southeast Asia,

and Central America.

Sedentary Lifestyle Physical inactivity and less cardiorespiratory

fitness are predictors of CVD events and the related risk of death.

Many components of the metabolic syndrome are associated with a

sedentary lifestyle, including increased adipose tissue (predominantly

central), reduced HDL cholesterol, and increased triglycerides, blood

pressure, and glucose in genetically susceptible persons. Compared

with individuals who watch television or videos or use the computer

<1 h daily, those who do so for >4 h daily have a twofold increased risk

of the metabolic syndrome.

Genetics No single gene explains the complex phenotype called the

metabolic syndrome. However, using genome-wide association and

candidate gene approaches, several genetic variants are associated with

the metabolic syndrome. Although many of the loci have unknown

function, many others relate to body weight and composition, insulin resistance, and unfavorable disturbances in lipid and lipoprotein

metabolism.

Aging The metabolic syndrome affects nearly 50% of the U.S.

population aged >60, and at >60 years of age, women are more often

affected. The age dependency of the syndrome’s prevalence is seen in

most populations around the world.

Diabetes Mellitus Diabetes mellitus can be included in both the

NCEP and the harmonizing definitions of the metabolic syndrome,

but the greatest value of the metabolic syndrome, and especially fasting

glucose, is predicting type 2 diabetes. The great majority (~75%) of

patients with type 2 diabetes or impaired glucose tolerance have the

metabolic syndrome. The presence of the metabolic syndrome in these

populations relates to a higher prevalence of CVD than in patients who

have type 2 diabetes or impaired glucose tolerance but do not have the

syndrome.

Cardiovascular Disease Individuals with the metabolic syndrome are twice as likely to die of CVD as those who do not, and their

risk of an acute myocardial infarction or stroke is threefold higher. The

approximate prevalence of the metabolic syndrome among patients

with coronary heart disease (CHD) is 60%, with a prevalence of ~35%

among patients with premature coronary artery disease (age ≤45) and a

particularly high prevalence among women. With appropriate cardiac

rehabilitation and changes in lifestyle (e.g., nutrition, physical activity,

weight reduction, and—in some cases—pharmacologic therapy), the

prevalence of the syndrome can be reduced.

Lipodystrophy Lipodystrophic disorders in general are associated with the metabolic syndrome. Moreover, it is quite common for

such patients to present with the metabolic syndrome. Both genetic

TABLE 408-1 NCEP:ATPIIIa

 2001 and Harmonizing Definition Criteria for the Metabolic Syndrome

NCEP:ATPIII 2001 HARMONIZING DEFINITIONb

Three or more of the following:

• Central obesity: waist circumference >102 cm (males),

>88 cm (females)

• Hypertriglyceridemia: triglyceride level ≥150 mg/dL or

specific medication

• Low HDLc

 cholesterol: <40 mg/dL and <50 mg/dL for

men and women, respectively, or specific medication

• Hypertension: blood pressure ≥130 mmHg systolic or

≥85 mmHg diastolic or specific medication

• Fasting plasma glucose level ≥100 mg/dL or specific

medication or previously diagnosed type 2 diabetes

Three of the following:

Waist circumference (cm)

Men Women Ethnicity

≥94 ≥80 Europid, sub-Saharan African, Eastern and Middle Eastern

≥90 ≥80 South Asian, Chinese, and ethnic South and Central American

≥85 ≥90 Japanese

• Fasting triglyceride level >150 mg/dL or specific medication

• HDL cholesterol level <40 mg/dL and <50 mg/dL for men and women, respectively, or specific medication

• Blood pressure >130 mm systolic or >85 mm diastolic or previous diagnosis or specific medication

• Fasting plasma glucose level ≥100 mg/dL (alternative indication: drug treatment of elevated glucose levels)

a

National Cholesterol Education Program and Adult Treatment Panel III. b

In this analysis, the following thresholds for waist circumference were used: white men,

≥94 cm; African-American men, ≥94 cm; Mexican-American men, ≥90 cm; white women, ≥80 cm; African-American women, ≥80 cm; Mexican-American women, ≥80 cm. For

participants whose designation was “other race—including multiracial,” thresholds that were once based on Europid cutoffs (≥94 cm for men and ≥80 cm for women) and

on South Asian cutoffs (≥90 cm for men and ≥80 cm for women) were used. For participants who were considered “other Hispanic,” the International Diabetes Federation

thresholds for ethnic South and Central Americans were used. c

High-density lipoprotein.

lipodystrophy (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophy) and acquired lipodystrophy

(e.g., HIV-related lipodystrophy and in HIV patients receiving certain

antiretroviral therapies) may give rise to severe insulin resistance and

many of the components of the metabolic syndrome.

■ ETIOLOGY

Insulin Resistance The most accepted and unifying hypothesis

to describe the pathophysiology of the metabolic syndrome is insulin

resistance, caused systemically by an incompletely understood defect in

insulin action (Chap. 403). The onset of insulin resistance is heralded

by postprandial hyperinsulinemia, which is followed by fasting hyperinsulinemia and ultimately by hyperglycemia.

An early major contributor to the development of insulin resistance

is an overabundance of circulating fatty acids (Fig. 408-2). Plasma

albumin-bound free fatty acids are derived predominantly from

adipose-tissue triglyceride stores released by intracellular lipolytic

enzymes. The lipolysis of triglyceride-rich lipoproteins in tissues by

lipoprotein lipase also produces free fatty acids. Insulin mediates both

anti-lipolysis and the stimulation of lipoprotein lipase in adipose tissue.

Of note, the inhibition of lipolysis in adipose tissue is the most sensitive pathway of insulin action. Thus, when insulin resistance develops,

increased lipolysis produces more fatty acids, which further decrease

the anti-lipolytic effect of insulin. Excessive fatty acids enhance substrate availability and create insulin resistance by modifying downstream signaling. Fatty acids impair insulin-mediated glucose uptake

and accumulate as triglycerides in both skeletal and cardiac muscle,

whereas increased fatty acid flux increases glucose production and

triglyceride production and accumulation in the liver.

Leptin resistance also may be a pathophysiologic mechanism

to explain the metabolic syndrome. Physiologically, leptin reduces

appetite, promotes energy expenditure, and enhances insulin sensitivity when insulin resistance is associated with leptin deficiency. In

addition, leptin may regulate cardiac and vascular function through

a nitric oxide–dependent mechanism. However, when obesity develops, hyperleptinemia ensues, with evidence of leptin resistance in the

brain and other tissues resulting in inflammation, insulin resistance,

hyperlipidemia, and a plethora of cardiovascular disorders, such as

hypertension, atherosclerosis, CHD, and heart failure.

The oxidative stress hypothesis provides a unifying theory for

aging and the predisposition to the metabolic syndrome. In studies of

insulin-resistant individuals with obesity or type 2 diabetes, the offspring of patients with type 2 diabetes, and the elderly, a defect in

mitochondrial oxidative phosphorylation leads to the accumulation of

triglycerides and related lipid molecules in muscle, liver, and perhaps

other tissues, i.e., β-cells.

Recently, the gut microbiome has emerged as an important contributor to the development of obesity and related metabolic disorders,

3152 PART 12 Endocrinology and Metabolism

18–29 y

30–49 y

50–69 y

>70 y

80

70

60

% With metabolic syndrome

C

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

D

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

E

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

F

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

G

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

H

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

A

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

80

70

60

% With metabolic syndrome

B

50

40

30

20

10

0

1988–1994 1999–2006

NHANES time period

2007–2012

Non-Hispanic white women

Non-Hispanic black women

Mexican American women

Standard error

Non-Hispanic white men

Non-Hispanic black men

Mexican American men

Standard error

FIGURE 408-1 Prevalence of metabolic syndrome among US adults over time by race/ethnicity-sex and age group, National Health and Nutrition Examination Survey

(NHANES), 1988-2012. Metabolic syndrome was defined by using the criteria agreed to jointly by the International Diabetes Federation; the US National Heart, Lung, and

Blood Institute in the United States; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study

of Obesity SE, standard error. (Reproduced with permission from JX Moore, N Chaudhary, T Akinyemiju. Metabolic syndrome prevalence by race/ethnicity and sex in the

United States, National Health and Nutrition Examination Survey, 1988-2012. Prev Chronic Dis 14:E24, 2017.)

3153The Metabolic Syndrome CHAPTER 408

including inflammation and components of the metabolic syndrome.

Although the mechanisms remain uncertain, interaction among

genetic predisposition, diet, bile acid metabolism, and the intestinal

flora is important.

Increased Waist Circumference Waist circumference is an

important component of the most recent and frequently applied diagnostic criteria for the metabolic syndrome. However, measuring waist

circumference does not reliably distinguish increases in SC abdominal

adipose tissue from that in visceral fat; this distinction requires CT or

MRI. With increases in visceral adipose tissue, adipose tissue–derived

free fatty acids reach the liver more readily. In contrast, increases in

abdominal SC fat release lipolysis products into the systemic circulation and therefore have fewer direct effects on hepatic metabolism.

Relative increases in visceral versus SC adipose tissue with increasing waist circumference in Asians and Asian Indians may explain

the greater prevalence of the syndrome in those populations than in

African-American men, in whom SC fat predominates. It is also possible that visceral fat is a marker for—but not the source of—excess

postprandial free fatty acids in obesity.

Dyslipidemia (See also Chap. 407) In general, free fatty acid flux

to the liver results in increased production of apolipoprotein (apo) B–

containing, triglyceride-rich, very-low-density lipoproteins (VLDLs).

The effect of insulin on this process is complex, but hypertriglyceridemia is an excellent marker of the insulin-resistant condition. Not

only is hypertriglyceridemia a feature of the metabolic syndrome, but

patients with the metabolic syndrome have elevated levels of apoC-III

carried on VLDLs and other lipoproteins. This increase in apoC-III is

inhibitory to lipoprotein lipase, reduces triglyceride-rich lipoprotein

remnant removal further contributing to hypertriglyceridemia, and

confers more risk for atherosclerotic cardiovascular disease (ASCVD).

The other major lipoprotein disturbance in the metabolic syndrome

is a reduction in HDL cholesterol. This reduction is a consequence

of changes in HDL composition and metabolism. In the presence of

hypertriglyceridemia, a decrease in the cholesterol content of HDL is

a consequence of reduced cholesteryl ester content of the lipoprotein

core in combination with cholesteryl ester transfer protein–mediated

alterations in triglycerides that make the HDL particle small and

dense. This change in lipoprotein composition also results in increased

clearance of HDL from the circulation. These changes in HDL have a

relationship to insulin resistance that is probably indirect, occurring in

concert with the changes in triglyceride-rich lipoprotein metabolism.

In addition to HDLs, low-density lipoproteins (LDLs) have alterations in composition in the metabolic syndrome. With fasting serum

triglycerides at >2.0 mM (~180 mg/dL), there is usually a predominance of small dense LDLs, which are thought to be more atherogenic,

although their association with hypertriglyceridemia and low HDLs

make their independent contribution to ASCVD difficult to assess.

Individuals with hypertriglyceridemia often have increases in cholesterol content of both VLDL1 and VLDL2 subfractions and in LDL particle number. Both lipoprotein changes may contribute to atherogenic

risk in patients with the metabolic syndrome.

Glucose Intolerance (See also Chap. 403) Defects in insulin

action in the metabolic syndrome lead to impaired suppression of

glucose production by the liver (and kidney) and reduced glucose

uptake and metabolism in insulin-sensitive tissues—i.e., muscle and

adipose tissue. There is a strong relationship between impaired fasting

– – –

Hypertension

FFA

HDL cholesterol

Small dense LDL

C-III

C-II

B-100 and

VLDL

CRP

FFA

PAI-1 Adiponectin

FFA

Triglyceride

(intramuscular

droplet)

Glycogen

Glucose

TNF-α

IL-6

CO2

Fibrinogen

Prothrombotic

state

TG Insulin

Insulin

IL-6 SNS

FIGURE 408-2 Pathophysiology of the metabolic syndrome. Free fatty acids (FFAs) are released in abundance from an expanded adipose tissue mass. In the liver, FFAs

result in increased production of glucose and triglycerides and secretion of very-low-density lipoproteins (VLDLs). Associated lipid/lipoprotein abnormalities include

reductions in high-density lipoprotein (HDL) cholesterol and an increased low-density lipoprotein (LDL) particle number. FFAs also reduce insulin sensitivity in muscle by

inhibiting insulin-mediated glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increased lipid accumulation in triglyceride

(TG). The increase in circulating glucose, and to some extent FFAs, increases pancreatic insulin secretion, resulting in hyperinsulinemia. Hyperinsulinemia may result in

enhanced sodium reabsorption and increased sympathetic nervous system (SNS) activity and contribute to hypertension, as might higher levels of circulating FFAs. The

proinflammatory state is superimposed and contributory to the insulin resistance produced by excessive FFAs. The enhanced secretion of interleukin 6 (IL-6) and tumor

necrosis factor α (TNF-α) produced by adipocytes and monocyte-derived macrophages results in more insulin resistance and lipolysis of adipose tissue triglyceride stores

to circulating FFAs. IL-6 and other cytokines also enhance hepatic glucose production, VLDL production by the liver, hypertension, and insulin resistance in muscle. Insulin

resistance also contributes to increased triglyceride accumulation in the liver (nonalcoholic fatty liver disease). Cytokines and FFAs also increase hepatic production of

fibrinogen and adipocyte production of plasminogen activator inhibitor 1 (PAI-1), resulting in a pro-thrombotic state. Higher levels of circulating cytokines stimulate hepatic

production of C-reactive protein (CRP). Reduced production of the anti-inflammatory and insulin-sensitizing cytokine adiponectin is also associated with the metabolic

syndrome. (Reproduced with permission from RH Eckel et al: The metabolic syndrome. Lancet 365:1415, 2005.)

3154 PART 12 Endocrinology and Metabolism

glucose or impaired glucose tolerance and insulin resistance in studies of humans, nonhuman primates, and rodents. To compensate for

defects in insulin action, insulin secretion and/or clearance increases

or decreases, respectively, so that euglycemia remains. Ultimately, this

compensatory mechanism fails because of defects in insulin secretion,

resulting in progression from impaired fasting glucose and/or impaired

glucose tolerance to type 2 diabetes mellitus.

Hypertension The relationship between insulin resistance and

hypertension is well established. Paradoxically, under normal physiologic conditions, insulin is a vasodilator with secondary effects on

sodium reabsorption in the kidney. However, in the setting of insulin

resistance, the vasodilatory effect of insulin is lost but the renal effect

on sodium reabsorption is preserved. Sodium reabsorption is increased

in Caucasians with the metabolic syndrome but not in Africans or

Asians. Insulin also increases the activity of the sympathetic nervous

system, an effect that is preserved in the setting of insulin resistance.

Insulin resistance is also associated with pathway-specific impairment

in phosphatidylinositol-3-kinase signaling. In the endothelium, this

impairment may cause an imbalance between the production of nitric

oxide and the secretion of endothelin 1, with a consequent decrease in

blood flow. In addition, increases in angiotensinogen gene expression

in adipose tissue of obese subjects results in increases in circulating

angiotensin II and vasoconstriction. Although these mechanisms are

provocative, the inadequate evaluation of insulin action by measurement of fasting insulin levels or by homeostasis model assessment

shows that insulin resistance contributes only partially to the increased

prevalence of hypertension in the metabolic syndrome.

Another possible mechanism underlying hypertension in the metabolic syndrome is the vasoactive role of perivascular adipose tissue.

Reactive oxygen species released by NADPH oxidase impair endothelial function and result in local vasoconstriction. Other paracrine

effects such as leptin or other proinflammatory cytokines released

from adipose tissue, such as tumor necrosis factor α (TNF-α) may also

be important.

Hyperuricemia is another consequence of insulin resistance in the

metabolic syndrome. There is growing evidence not only that uric acid

is associated with hypertension but also that reduction of uric acid

normalizes blood pressure in hyperuricemic adolescents with hypertension. The mechanism appears to be in part related to an adverse

effect of uric acid on nitric oxide synthase in the macula densa of the

kidney and stimulation of the renin-angiotensin-aldosterone system.

Proinflammatory Cytokines The increases in proinflammatory

cytokines—including interleukins 1, 6, and 18; resistin; TNF-α; and

the systemic biomarker C-reactive protein—reflect overproduction by

the expanded adipose tissue mass (Fig. 408-2). Adipose tissue–derived

macrophages may be the primary source of proinflammatory cytokines

locally and in the systemic circulation. It remains unclear, however,

how much of the insulin resistance is caused by the paracrine effects of

these cytokines and how much by the endocrine effects.

Adiponectin Adiponectin is an anti-inflammatory cytokine produced exclusively by adipocytes. Adiponectin enhances insulin sensitivity and inhibits many steps in the inflammatory process. In the liver,

adiponectin inhibits the expression of gluconeogenic enzymes and the

rate of glucose production. In muscle, adiponectin increases glucose

transport and enhances fatty acid oxidation, partially through the activation of AMP kinase. Reductions in adiponectin levels are common

in the metabolic syndrome. The relative contributions of adiponectin

deficiency and overabundance of the proinflammatory cytokines are

unclear.

■ CLINICAL FEATURES

Symptoms and Signs The metabolic syndrome typically is not

associated with symptoms. On physical examination, waist circumference and blood pressure are often elevated. The presence of either or

both signs should prompt the clinician to search for other biochemical

abnormalities that may be associated with the metabolic syndrome.

Much less frequently, lipoatrophy or acanthosis nigricans is present

on examination. Because these physical findings characteristically are

associated with severe insulin resistance, other components of the metabolic syndrome are much more common.

Associated Diseases • CARDIOVASCULAR DISEASE The relative risk for new-onset CVD in patients with the metabolic syndrome

who do not have diabetes averages 1.5- to 3-fold. However, in INTERHEART, a study of 26,903 subjects from 52 countries, the risk for acute

myocardial infarction in subjects with the metabolic syndrome (World

Health Organization or International Diabetes Federation definition)

is comparable to that conferred by some, but not all, of the component

risk factors. Diabetes mellitus (odds ratio [OR], 2.72) and hypertension

(OR, 2.60) are stronger than other risk factors. Although congestive

heart failure and the metabolic syndrome can occur together, typically

this consequence is secondary to metabolic syndrome–related ASCVD

or hypertension. Metabolic syndrome is also associated with increases

in the risk for stroke, peripheral vascular disease, and Alzheimer’s

disease. However, as for myocardial infarction, the risk beyond the

additive role of the components of the metabolic syndrome remains

debatable. In the Reasons for Geographic and Racial Differences in

Stroke (REGARDS) cohort, an observational study of black and white

adults ≥45 years old across the United States, there were 9741 participants, and 41% had the metabolic syndrome. After adjustment for multiple confounders, metabolic syndrome was associated with increases

in high-sensitivity C-reactive protein (hsCRP), and this relationship

was associated with a 1.34 relative risk for all-cause mortality, but <50%

of deaths were from CVD. The population-attributable risk was 9.5%

for the metabolic syndrome alone and 14.7% for both metabolic syndrome and increased hsCRP. The relationship of metabolic syndrome

and hsCRP to mortality was greater for whites than blacks.

TYPE 2 DIABETES Overall, the risk for type 2 diabetes among patients

with the metabolic syndrome is increased three- to fivefold. In the

Framingham Offspring Study’s 8-year follow-up of middle-aged participants, the population-attributable risk of the metabolic syndrome

for developing type 2 diabetes was 62% among men and 47% among

women, yet increases in fasting plasma glucose explained most, if not

all, of this increased risk.

Other Associated Conditions In addition to the features specifically used to define the metabolic syndrome, other metabolic

alterations are secondary to or accompany insulin resistance. Those

alterations include increases in apoB and apoC-III, uric acid, prothrombotic factors (fibrinogen, plasminogen activator inhibitor 1),

serum viscosity, asymmetric dimethylarginine, homocysteine, white

blood cell count, proinflammatory cytokines, C-reactive protein, urine

albumin/creatinine ratio, nonalcoholic fatty liver disease (NAFLD)

and/or nonalcoholic steatohepatitis (NASH), polycystic ovary syndrome, and obstructive sleep apnea.

NONALCOHOLIC FATTY LIVER DISEASE NAFLD has become the most

common liver disease, in part a consequence of the insulin resistance

of the metabolic syndrome. The mechanism relates to increases in

free fatty acid flux and reductions in intrahepatic fatty acid oxidation

with resultant increases in triglyceride biosynthesis and hepatocellular

accumulation, with variable inflammation and oxidative stress. The

more serious NASH, a consequence of NAFLD in some patients and

a precursor of cirrhosis and end-stage liver disease, includes a more

substantial proinflammatory contribution. NAFLD affects ~25% of

the global population and up to 45% of patients with the metabolic

syndrome; over half of these patients have NASH. As the prevalence of

overweight/obesity and the metabolic syndrome increases, NASH may

become one of the more common causes of end-stage liver disease and

hepatocellular carcinoma.

HYPERURICEMIA (See also Chap. 417) Hyperuricemia reflects defects

in insulin action on the renal tubular reabsorption of uric acid and may

contribute to hypertension through its effect on the endothelium. An

increase in asymmetric dimethylarginine, an endogenous inhibitor

of nitric oxide synthase, also relates to endothelial dysfunction. In

addition, increases in the urine albumin/creatinine ratio may relate to

altered endothelial pathophysiology in the insulin-resistant state.

3155The Metabolic Syndrome CHAPTER 408

POLYCYSTIC OVARY SYNDROME (See also Chap. 392) Polycystic

ovary syndrome is highly associated with insulin resistance (50–80%)

and the metabolic syndrome, with a prevalence of the syndrome

between 12 and 60% based on phenotypes D through A.

OBSTRUCTIVE SLEEP APNEA (See also Chap. 31) Obstructive sleep

apnea is commonly associated with obesity, hypertension, increased

circulating cytokines, impaired glucose tolerance, and insulin resistance. In fact, obstructive sleep apnea may predict metabolic syndrome,

even in the absence of excess adiposity. Moreover, when biomarkers of

insulin resistance are compared between patients with obstructive

sleep apnea and weight-matched controls, insulin resistance is found to

be more severe in those with apnea. Continuous positive airway pressure treatment improves insulin sensitivity in patients with obstructive

sleep apnea.

■ DIAGNOSIS

The diagnosis of the metabolic syndrome relies on fulfillment of the

criteria listed in Table 408-1, as assessed using tools at the bedside and in

the laboratory. The medical history should include evaluation of symptoms for obstructive sleep apnea in all patients and polycystic ovary

syndrome in premenopausal women. Family history will help determine

risk for CVD and diabetes mellitus. Blood pressure and waist circumference measurements provide information necessary for the diagnosis.

Laboratory Tests Measurement of fasting lipids and glucose is

needed in determining whether the metabolic syndrome is present.

The measurement of additional biomarkers associated with insulin

resistance can be individualized. Such tests might include those for

apoB, hsCRP, fibrinogen, uric acid, urinary albumin/creatinine ratio,

and liver function. A sleep study should be performed if symptoms

of obstructive sleep apnea are present. If polycystic ovary syndrome

is suspected based on clinical features and anovulation, testosterone,

luteinizing hormone, and follicle-stimulating hormone should be measured. NAFLD can be further assessed by the NAFLD fibrosis score

(FIB4) or elastography.

TREATMENT

The Metabolic Syndrome

LIFESTYLE (SEE ALSO CHAP. 402)

Obesity, particularly abdominal, is the driving force behind the

metabolic syndrome. Thus, weight reduction is the primary

approach to the disorder. With at least a 5% and more so with

10% weight reduction, improvement in insulin sensitivity results

in favorable modifications in many components of the metabolic

syndrome. In general, recommendations for weight loss include a

combination of caloric restriction, increased physical activity, and

behavior modification. Caloric restriction is the most important

component, whereas increases in physical activity are important

for maintenance of weight loss. Some but not all evidence suggests

that the addition of exercise to caloric restriction may promote

greater weight loss from the visceral depot. The tendency for weight

regain after successful weight reduction underscores the need for

long-lasting behavioral changes.

Diet Before prescribing a weight-loss diet, it is important to

emphasize that it has taken the patient a long time to develop an

expanded fat mass; thus, the correction need not occur quickly.

Given that ~3500 kcal = 1 lb of fat, an ~500-kcal restriction daily

equates to weight reduction of 1 lb per week. Diets restricted in carbohydrate typically provide a more rapid initial weight loss. However, after 1 year, the amount of weight reduction is minimally more

reduced or no different from that with caloric restriction alone.

Thus, adherence to the diet is more important than the chosen diet.

Moreover, there is concern about low-carbohydrate diets enriched

in saturated fat, particularly for patients at risk for ASCVD. Therefore, a high-quality dietary pattern—i.e., a diet enriched in fruits,

vegetables, whole grains, lean poultry, and fish—should be encouraged to maximize overall health benefit.

Physical Activity Before prescribing a physical activity program

to patients with the metabolic syndrome, it is important to ensure

that the increased activity does not incur risk. Some high-risk

patients should undergo formal cardiovascular evaluation before

initiating an exercise program. For an inactive participant, gradual

increases in physical activity should be encouraged to enhance

adherence and avoid injury. Although increases in physical activity

can lead to modest weight reduction, 60–90 min of moderate- to

high-intensity daily activity is required to achieve this goal. Even

if an overweight or obese adult is unable to undertake this level of

activity, a health benefit will follow from at least 30 min of moderate-intensity activity daily. The caloric value of 30 min of a variety of

activities can be found at https://www.health.harvard.edu/diet-andweight-loss/calories-burned-in-30-minutes-of-leisure-and-routineactivities. Of note, a variety of routine activities, such as gardening,

walking, and housecleaning, require moderate caloric expenditure.

Thus, physical activity should not be defined solely in terms of formal exercise such as jogging, swimming, or tennis.

Behavior Modification Behavioral treatment typically includes

recommendations for dietary restriction and more physical activity that predicts sufficient weight loss that benefits metabolic

health. The subsequent challenge is the duration of the program

because weight regain so often follows successful weight reduction.

Improved long-term outcomes often follow a variety of methods,

such as a personal or group counselor, the Internet, social media,

and telephone follow-up to maintain contact between providers

and patients.

Obesity (See also Chap. 402) In some patients with the metabolic syndrome, treatment options need to extend beyond lifestyle

intervention. Weight-loss drugs come in two major classes: appetite

suppressants and absorption inhibitors. Appetite suppressants

approved by the U.S. Food and Drug Administration (FDA)

include phentermine (for short-term use [3 months] only) as well

as the more recent additions phentermine/topiramate, naltrexone/

bupropion, high-dose (3.0 mg) liraglutide (rather than 1.8 mg, the

maximum for treatment of type 2 diabetes), semaglutide (2.4 mg)

which are approved without restrictions on the duration of therapy.

In clinical trials, the phentermine/topiramate extended-release

combination resulted in ~8% weight loss relative to placebo in 50%

of patients. Side effects include palpitations, headache, paresthesias, constipation, and insomnia. Naltrexone/bupropion extended

release reduces body weight by ≥10% in ~20% of patients; however,

the drug combination is contraindicated in patients with seizure

disorders or any condition that predisposes to seizures. Naltrexone/

bupropion also increases pulse and blood pressure and should not

be given to patients with uncontrolled hypertension. High-dose

liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist,

results in ~6% weight loss relative to placebo with ~33% of patients

with >10% weight loss. Common side effects are limited to the

upper gastrointestinal tract, including nausea and, less frequently,

emesis. Semaglutide (2.4 mg weekly), recently FDA approved

has been shown to produce an average weight loss of 14.9% over

68 weeks.

Orlistat inhibits fat absorption by ~30% and is moderately effective compared with placebo (~4% more weight loss). Moreover,

orlistat reduced the incidence of type 2 diabetes, an effect that was

especially evident among patients with impaired glucose tolerance

at baseline. This drug is often difficult to take because of oily leakage per rectum. In general, for all weight-loss drugs, greater weight

reduction leads to greater improvement in metabolic syndrome

components, including the conversion from prediabetes to type 2

diabetes.

Metabolic or bariatric surgery is an important option for patients

with the metabolic syndrome who have a body mass index of

>40 kg/m2

 or >35 kg/m2

 with comorbidities. An evolving application for metabolic surgery includes patients with a body mass

index as low as 30 kg/m2

 and type 2 diabetes. Gastric bypass or

vertical sleeve gastrectomy results in dramatic weight reduction

3156 PART 12 Endocrinology and Metabolism

and improvement in most features of the metabolic syndrome. A

survival benefit with gastric bypass has also been realized.

LDL CHOLESTEROL (SEE ALSO CHAP. 407)

The rationale for the development of criteria for the metabolic syndrome by NCEP was to go beyond LDL cholesterol in identifying

and reducing the risk of ASCVD. The working assumption by the

panel was that LDL cholesterol goals had already been achieved

and that increasing evidence supports a linear reduction in ASCVD

events because of progressive lowering of LDL cholesterol with

statins with subsequent benefit using additional LDL cholesterol–

lowering agents. The 2019 American College of Cardiology (ACC)/

American Health Association (AHA) Cholesterol Guidelines have

no specific recommendations for patients with the metabolic syndrome; however, they recommend that patients aged 20–75 years

with LDL cholesterol levels ≥190 mg/dL should use a high-intensity

statin (e.g., atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily)

and those with type 2 diabetes aged 40–75 years should use a

moderate-intensity statin and, if or when risk estimate is high, a

high-intensity statin. For patients with the metabolic syndrome

but without diabetes, the 10-year ASCVD risk estimator should

be employed, and patients with a risk ≥7.5% and ≤20% or patients

aged 20–59 with elevated lifetime risk should have a discussion

with their provider about initiating statin therapy for primary prevention of ASCVD. A coronary calcium score may help in making

this decision.

Diets restricted in saturated fats (<6% of calories) and trans

fats (as few as possible) should be applied aggressively. Although

evidence is controversial, dietary cholesterol can also be restricted.

If LDL cholesterol remains elevated, pharmacologic intervention

is needed. Based on substantial evidence, treatment with statins,

which lower LDL cholesterol by 15–60%, is the first-choice medication intervention. Of note, for each doubling of the statin dose,

LDL cholesterol is further lowered by only ~6%. Hepatotoxicity

(more than a threefold increase in hepatic aminotransferases) is

rare, but myopathy occurs in ~10–20% of patients. The cholesterol

absorption inhibitor ezetimibe is well tolerated and should be the

second-choice medication intervention. Ezetimibe typically reduces

LDL cholesterol by 15–20%. Bempedoic acid alone or in combination with ezetimibe is another option, with up to a 35% lowering

of LDL cholesterol with the combination. Bempedoic acid can

increase plasma uric acid. Proprotein convertase subtilisin/kexin

type 9 (PCSK9) inhibitors are potent LDL cholesterol–lowering

drugs (~45–60%) but are not needed for most patients with the

metabolic syndrome. Of course, if these patients also have familial

hypercholesterolemia or insufficient LDL cholesterol lowering on

statins with or without ezetimibe, a PCSK9 inhibitor should be

considered. The bile acid sequestrants cholestyramine, colestipol,

and colesevelam may be more effective than ezetimibe alone, but

because they can increase triglyceride levels, they must be used

with caution in patients with the metabolic syndrome when fasting

triglycerides are >300 mg/dL. Side effects include gastrointestinal

symptoms (palatability, bloating, belching, constipation, anal irritation). Nicotinic acid has similar LDL cholesterol–lowering capabilities (<20%). Fibrates are best employed to lower LDL cholesterol

when triglycerides are not elevated. Fenofibrate may be more effective than gemfibrozil in this setting.

TRIGLYCERIDES (SEE ALSO CHAP. 407)

The 2019 ACC/AHA Cholesterol Guidelines stated that fasting

triglycerides >500 mg/dL should be treated to prevent more serious

hypertriglyceridemia and pancreatitis. Although a fasting triglyceride value of >150 mg/dL is a component of the metabolic syndrome,

post hoc analyses of multiple fibrate trials have suggested reduction in the primary ASCVD outcome in patients (with or without

concomitant statin therapy) with fasting triglycerides >200 mg/dL,

often in the setting of reduced levels of HDL cholesterol. It remains

uncertain whether triglycerides cause ASCVD or if levels are just

associated with increased ASCVD risk.

A fibrate (gemfibrozil or fenofibrate) is one drug class of choice

to lower fasting triglyceride levels, which are typically reduced by

30–45%. Concomitant administration with drugs metabolized by the

3A4 cytochrome P450 system (including some statins) increases the

risk of myopathy. In these cases, fenofibrate may be preferable to gemfibrozil. In the Veterans Affairs HDL Intervention Trial, gemfibrozil was

administered to men with known CHD and levels of HDL cholesterol

<40 mg/dL. A coronary disease event and mortality rate benefit was

experienced predominantly among men with hyperinsulinemia and/

or diabetes, many of whom were identified retrospectively as having

the metabolic syndrome. Of note, the degree of triglyceride lowering in

this trial or other fibrate trials did not predict benefit.

Other drugs that lower triglyceride levels include statins, nicotinic acid, and prescription omega-3 fatty acids. For this purpose,

an intermediate or high dose of the “more potent” statins (atorvastatin, rosuvastatin) is needed. The effect of nicotinic acid on

fasting triglycerides is dose related and ~20–35%, an effect that is

less pronounced than that of fibrates. In patients with the metabolic

syndrome and diabetes, nicotinic acid may increase fasting glucose

levels, and clinical trials with nicotinic acid plus a statin have failed

to reduce ASCVD events. Prescriptions of omega-3 fatty acid preparations that include high doses of eicosapentaenoic acid (EPA)

with or without docosahexaenoic acid (DHA) (~1.5–4.5 g/d) lower

fasting triglyceride levels by ~25–40%. The two omega-3 randomized controlled trials associated with ASCVD risk reduction, JELIS

and REDUCE-IT, used EPA only, whereas STRENGTH, which was

terminated prematurely because of futility, used EPA plus DHA.

Here, no drug interactions with fibrates or statins occur, and the

main side effect of their use is eructation with a fishy taste. Freezing

the nutraceutical can partially block this unpleasant side effect.

Importantly, lowering triglycerides with any of the pharmaceuticals

has not proven to be an independent predictor of CVD outcomes.

HDL CHOLESTEROL (SEE ALSO CHAP. 407)

Very few lipid-modifying compounds increase HDL cholesterol levels. Statins, fibrates, and bile acid sequestrants have modest effects

(5–10%), whereas ezetimibe and omega-3 fatty acids have no effect.

Nicotinic acid is the only currently available drug with predictable

HDL cholesterol–raising properties. The response is dose related,

and nicotinic acid can increase HDL cholesterol by up to 30%

above baseline. After several trials of nicotinic acid versus placebo

in statin-treated patients, there is no evidence that raising HDL

cholesterol with nicotinic acid beneficially affects ASCVD events in

patients with or without the metabolic syndrome.

BLOOD PRESSURE (SEE ALSO CHAP. 277)

The direct relationship between blood pressure and all-cause mortality rate has been well established in studies comparing patients

with hypertension (>140/90 mmHg), patients with prehypertension (>120/80 mmHg but <140/90 mmHg), and individuals with

normal blood pressure (<120/80 mmHg). In patients who have the

metabolic syndrome without diabetes, the best choice for the initial

antihypertensive medication is an angiotensin-converting enzyme

(ACE) inhibitor or an angiotensin II receptor blocker, as these two

classes of drugs are effective and well tolerated. Additional agents

include a diuretic, calcium channel blocker, beta blocker, and mineralocorticoid inhibitor, such as the recently FDA approved mineralocorticoid receptor antagonist finerenone. In all patients with

hypertension, a sodium-restricted dietary pattern enriched in fruits

and vegetables, whole grains, and low-fat dairy products should be

advocated. Home monitoring of blood pressure may assist in maintaining good blood pressure control.

IMPAIRED FASTING GLUCOSE (SEE ALSO CHAP. 403)

In patients with the metabolic syndrome and type 2 diabetes,

aggressive glycemic control may favorably modify fasting levels

of triglycerides and/or HDL cholesterol. In patients with impaired

fasting glucose who do not have diabetes, a lifestyle intervention

that includes weight reduction, dietary saturated fat restriction, and

increased physical activity has been shown to reduce the incidence