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abstract
The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease and type 2 diabetes. It is composed
of atherogenic dyslipidemia, elevated blood pressure, insulin resistance and elevated glucose, a pro-thrombotic state, and a
pro-inflammatory state. Excess energy intake and concomitant obesity are the major drivers of the syndrome. Lifestyle
intervention can reverse metabolic risk factors, but at times, drug therapies or bariatric surgery may be required to control more overt
risk factors.
The metabolic syndrome is a multiplex risk factor for athero- includes both overt and borderline hypertension. Dysglyce-
sclerotic cardiovascular disease (ASCVD) and type 2 diabetes mia consists of either prediabetes or diabetes. Abnormalities
[1]. It doubles risk for ASCVD and, in patients without in coagulation factors and blood platelets make up a pro-
diabetes, increases risk for type 2 diabetes fivefold [2]. The thrombotic state. A pro-inflammatory state results from
metabolic syndrome occurs commonly throughout the world, inflammatory mediators acting on a variety of tissues. The
ranging in prevalence from 10% to 40% [3]. The syndrome contribution of each of these components to cardiovascular
occurs most often in populations characterized by excessive risk undoubtedly varies among individuals but, in combina-
nutrient intake and physical inactivity [4], but underlying tion, they double the risk for ASCVD.
metabolic and genetic susceptibilities are critical factors Several attempts have been made to craft a clinical defi-
as well. nition of the syndrome. The most commonly accepted is a
recent consensus definition [4] (Table). It includes abdominal
obesity as a key (but not necessary) component, elevations in
Definition of metabolic syndrome serum triglyceride and glucose, increased blood pressure, and
reduced levels of HDL cholesterol (HDL-C). The presence of
The metabolic syndrome consists of five factors for ASCVD: three or more of these constitutes a clinical diagnosis.
atherogenic dyslipidemia, elevated blood pressure, dysglyce-
mia, a pro-thrombotic state, and a pro-inflammatory state [5]
(Fig. 1). They occur most commonly in obese persons. Pathogenesis
Atherogenic dyslipidemia comprises elevations in plasma
triglycerides and apolipoprotein B (apo B), and reductions in An early hypothesis was that insulin resistance is the cause
high-density lipoproteins (HDL). Elevated blood pressure of metabolic syndrome [6,7]. Without question, insulin
This work was financially supported by the Center for Human Nutrition, UT Southwestern Medical Center, United States.
The author has indicated that there are no conflicts of interest.
n
Correspondence to: Department of Internal Medicine and Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry
Hines Bvd., Dallas, TX 75390-9052. Tel.: þ1 214 648 2890; fax: þ1 214 648 4837.
E-mail address: scott.grundy@utsouthwestern.edu (S.M. Grundy).
http://dx.doi.org/10.1016/j.tcm.2015.10.004
1050-1738/Published by Elsevier Inc.
T R E N D S I N C A R D I O V A S C U L A R ME D I C I N E 26 (2016) 364–373 365
intravascular volume, activations of the reninangiotensin with obesity is an increase in acute-phase reactants, such
aldosterone system and sympathetic nervous system, release as C-reactive protein [58]. Although an excess of adipose
of angiotensinogen from adipose tissue, and insulin resist- tissue per se may be responsible for low-grade inflammation,
ance [43,44]. The current consensus is that these factors act in overnutrition independent of obesity may also engender
conjunction to raise the blood pressure. inflammatory responses [59,60]. Cytokines released from
adipose tissue may induce insulin resistance in skeletal
Metabolic syndrome and stroke muscle [61], alter the pituitaryadrenal axis [62], and may
The metabolic syndrome doubles risk for stroke [45,46]. accelerate loss of pancreatic beta cells [63]. Finally, low-grade
Metabolic syndrome associates with both carotid atheroscle- inflammation within atherosclerotic lesions may increase the
rosis [47,48] and intracranial arteriosclerosis [49,50]. Presum- likelihood of plaque rupture, causing acute cardiovascular
ably the mechanisms for cerebral vascular disease are similar events [64].
to those for CHD.
Pro-thrombotic state
Hyperglycemia
Individuals with obesity and metabolic syndrome appear to
Prediabetes and diabetes have multiple abnormalities in the hemostatic system that
Most persons with the metabolic syndrome have some may well predispose to ASCVD. Among these are endothelial
elevation of plasma glucose [51]. This elevation can be in dysfunction, enhanced coagulation, impaired fibrinolysis, and
the range of either prediabetes or diabetes. Two patterns of platelet dysfunction [65,66]. Specific abnormalities include ele-
higher glucose define prediabetes: a fasting glucose in the vated levels of inhibitor of plasminogen activator type 1 [66,67],
range of 100125 mg/dL or a 2-h postprandial level of 140– tissue factor [68,69], fibrinogen [67], and factor VIII activity [70].
199 mg/dL. Categorical diabetes is defined as a fasting glucose Persons with metabolic syndrome have increased baseline
Z126 mg/dL or a postprandial level Z200 mg/dL. The primary platelet reactivity and a lower antiplatelet response to aspirin
cause of hyperglycemia in patients with metabolic syndrome [71]. Finally, it seems likely that patients with this syndrome are
is insulin resistance. However, otherwise normal persons at higher risk for venous thrombosis.
who are insulin resistant can avoid an elevated glucose by
compensatory hyperinsulinemia. Only when pancreatic beta-
cell function begins to decline do glucose levels start to rise. Management of metabolic syndrome
Thus, hyperglycemia typically is not the first indication of
metabolic syndrome, but develops as a later sequelae. In the Lifestyle intervention
consensus definition for metabolic syndrome (Table), both
prediabetes and diabetes count as metabolic risk factors. Most persons with metabolic syndrome are obese and sed-
entary. Urbanization and access to inexpensive foods are
Microvascular disease creating a metabolic syndrome pandemic [3]. Thus, primary
The primary clinical outcome of hyperglycemia is micro- intervention should be lifestyle change, i.e., caloric restric-
vascular disease, i.e., chronic kidney disease and diabetic tion, improved health quality of foods, and increased physical
retinopathy. In fact, type 2 diabetes is the foremost cause of activity.
chronic kidney disease. However, patients with diabetes
commonly have hypertension as well, which may accelerate Caloric restriction
the decline in kidney function. Microvascular disease may The most efficacious intervention is caloric restriction [9].
have widespread consequences beyond its effects on kidneys This can be achieved in several ways. Previously, very-low-
and eyes. It is likely that diabetic neuropathy is due in part to calorie diets (e.g., approximately 1000 cal per day) were tried.
microvascular disease [52]. Microvascular disease may fur- This approach was largely unsuccessful. Very rapid weight
ther accelerate development of congestive heart failure [53] loss is invariably followed by weight regain. The reason is a
and contribute to atherogenesis [54]. lack of behavioral change. A better way is behavioral mod-
ification combined with a low-calorie diet [5]. A team
Macrovascular disease approach is more effective, especially including a medical
The contribution of hyperglycemia to atherogenesis is uncer- nutrition therapist [72]. Of course, behavioral modification
tain. Certainly patients with diabetes are at increased risk for requires a lifetime commitment to dietary modification. For
ASCVD. Whether this excess risk can be explained by a direct many patients, this is a major challenge. Consequently, many
effect of hyperglycemia or concomitant metabolic risk factors social and environmental changes are necessary for success-
remains to be determined. ful weight loss. A reasonable first goal for the obese patient is
to reduce weight by approximately 10%. Further gradual
Pro-inflammatory state weight loss provides more benefit.
The composition of food intake must also be considered. A
A link between inflammation and metabolic diseases has low-fat/high-carbohydrate diet has been commonly recom-
been increasingly recognized. Obesity may underlie a low- mended, but a somewhat higher intake of unsaturated fat at
grade, systemic inflammation [55,56]. Macrophages invade the expense of carbohydrate may be more beneficial [73–75].
excess adipose tissue, resulting in the release of cytokines. Too much carbohydrate in the diet can worsen metabolic risk
They may trigger systemic inflammation [57]. Associated factors [76,77]. Most importantly, saturated fats should be
368 T R E N D S I N C A R D I O V A S C U L A R ME D I C I N E 26 (2016) 364–373
largely avoided; they will increase serum cholesterol levels Since the majority of persons with metabolic syndrome
and consequently will raise risk for ASCVD. have elevated plasma triglycerides, a persistent question has
If greater caloric restriction is needed, bariatric surgery can been whether triglyceride-lowering drugs might be beneficial
be considered. Obese patients with multiple risk factors (e.g., in this condition. Two such drugs have been employed: niacin
metabolic syndrome) are potential candidates for bariatric sur- and fibrates. In a large multicenter trial of secondary pre-
gery, especially if their body mass index is greater than 35 kg/m2 vention, niacin therapy decreased the occurrence of 6-year MI
[78]. Weight losses of 20% or more can be achieved. These losses and 15-year total mortality similarly among patients with or
have a favorable impact on all metabolic risk factors [26]. Of without the metabolic syndrome [89]. Multiple RCTs, which
course, clinical judgment is required to decide whether bariatric were enriched in patients with metabolic syndrome, show
surgery is appropriate for particular individuals. benefit from fibrate monotherapy in both primary and sec-
ondary prevention [90–93]. Risk reductions, however, usually
Regular physical activity are less than seen with statin therapy. Whether adding
Physical activity has several beneficial effects on metabolic triglyceride-lowering drugs to statins provides incremental
syndrome [79]. It favorably affects caloric balance; it reduces benefit is uncertain. In two studies [94,95], addition of niacin
insulin resistance; and it increases physical fitness, which to maximal dose statins failed to show further risk reduction.
appears to independently reduce risk for cardiovascular In another RCT in patients with diabetes, adding fenofibrate
disease [80,81]. Thus the introduction of a program of regular to statin therapy found no benefit [96]; but in a subgroup with
physical activity should be considered an integral part of hypertriglyceridemia, a nearly significant decrease in risk (p ¼
clinical management of metabolic syndrome. 0.06) was noted [97]. Thus, at present it is reasonable to add
fenofibrate to statin therapy in high-risk patients with meta-
Treatment of atherogenic dyslipidemia bolic syndrome; nonetheless, RCT evidence of benefit is
limited. Finally, in patients with type 2 diabetes, fenofibrate
Apo B-containing lipoproteins (both LDL and VLDL) are the appears to have a favorable effect on microvascular disease
primary target of dyslipidemia therapy. An acceptable meas- [98,99]; the mechanism for this benefit is not known. The
ure of these lipoproteins is non-HDL-C [82,83]. Available same drugs that lower triglyceride also raise HDL-C. The
ASCVD-outcome trials support the concept of “the lower, evidence of benefit from niacin and fibrates has been attrib-
the better” for reduction of atherogenic lipoproteins [84], but uted by some to raising HDL, but by others to lowering VLDL.
for practical consideration, the following “goals” have been RCTs are currently underway to test other HDL-raising drugs
proposed for non-HDL-C [85]. In secondary prevention, it is [100]; however, to date, the results of these trials have not
reasonable to reduce non-HDL-C to o100 mg/dL; in primary been reported. Regardless, a low HDL-C is a common finding
prevention, a reasonable goal is o130 mg/dL [85]. They in patients with metabolic syndrome and their levels can be
correspond to LDL-C reductions of o70 mg/dL and raised through lifestyle intervention. We must keep in mind
o 100 mg/dL, respectively. Ample clinical trial evidence exists that one of the benefits of maximum lifestyle intervention
in patients with metabolic syndrome to justify these target could result from an increase in HDL-C.
values [33–35]. Finally, in particularly high-risk patients with-
out ASCVD, reducing non-HDL-C to less than 100 mg/dL may Control of blood pressure
be prudent.
First-line treatment for non-HDL-C in metabolic syndrome The key therapy for hypertension in patients with metabolic
is statin therapy. Persons with this syndrome have a high- syndrome is caloric restriction. It has long been known that
lifetime-risk trajectory for ASCVD. For secondary prevention, reducing caloric intake will decrease blood pressure [101,102].
a non-HDL-C of o70 mg/dL is best achieved with high- Bariatric surgery is a particularly effective means of reducing
intensity statins (e.g., atorvastatin 80 mg or rosuvastatin blood pressure [103–105]. In addition to caloric restriction,
20–40 mg). However, some patients may not be able to modifying diet composition can facilitate blood pressure
tolerate high-intensity statins. If not, it is reasonable to add lowering. The so-called DASH diet was constructed for hyper-
ezetimibe to moderate-intensity statin (e.g., atorvastatin tensive patients [106]; this diet contains a favorable electro-
10 mg, rosuvastatin 5 mg, simvastatin 20 mg, or another lyte intake, caloric restriction, and reduction in saturated fat.
similar potency statin). These combinations produce the A recent modification of the DASH diet, resembling the
same non-HDL-C lowering as do maximum-intensity statins. Mediterranean diet, may be a more acceptable eating pattern
A recent secondary-prevention trial showed added risk for the United States [107]. This diet allows more total fat
reduction when ezetimibe was combined with a high- intake, provided the fat is unsaturated.
intensity statin [86]. This trial supports the “the lower, the A persistent question is whether certain anti-hypertensive
better” concept for atherogenic lipoproteins [84]. A new drugs are preferable for patients with obesity or metabolic
approach to reducing atherogenic lipoproteins is to use a syndrome. For example, some investigators [108,109] believe
monogenic antibody against PCSK9; the latter is a protein that ACE inhibitors or ARBs should be first-line therapy.
that facilitates the degradation of LDL receptors. Use of PCSK9 These agents do not induce insulin resistance or other
inhibitors induces a marked reduction in non-HDL-C. Pre- metabolic risk factors. In contrast, beta-1 receptor blockers
liminary evidence strongly suggests that they also reduce risk (e.g., atenolol and metoprolol) enhance insulin resistance and
for ASCVD [87,88]. Therefore, new alternatives are needed for potentially worsen the metabolic syndrome [110]. Conversely,
patients who are intolerant to statins or who are at very non-selective beta/alpha-1 receptor blockers (e.g., carvediol)
high risk. do not have these adverse metabolic effects, and when
T R E N D S I N C A R D I O V A S C U L A R ME D I C I N E 26 (2016) 364–373 369
indicated, appear to be preferable for patients with metabolic phospholipase A2, secretory phospholipase A2, intercellular
syndrome [111]. In addition, thiazide diuretics are known to adhesion molecule type 1, vascular cellular adhesion mole-
enhance insulin resistance [112]. Overall, both beta-blockers cule, plasminogen activator inhibitor type 1, serum amyloid A,
and thiazides reduce ASCVD, so clinical judgment is needed C-reactive protein, 5-lipoxygenase, sirtuin-1, and chemokine
whether to use one or both of these agents in patients with receptor types 2 and 5. These investigators further speculated
the metabolic syndrome. Finally, calcium channel blockers on potential agents that could impair inflammation acting on
appear to be metabolically neutral, or cause a slight improve- one or more of these targets. Examples include low-dose
ment of insulin resistance, and thus are acceptable drugs for methotrexate, various monoclonal antibodies, inhibitors of
those with metabolic syndrome [113,114]. adhesion molecules, and colchicine. A limited number of RCTs
An anti-hypertensive agent of biological interest is telmi- are either underway or being considered [125–127]. Although it
sartin, an angiotensin II receptor antagonist. This agent also is too early to know whether these approaches will reduce risk
acts as a selective modulator of peroxisome proliferator- for ASCVD, they have a theoretical basis for risk reduction in
activated receptor gamma (PPAR-γ), a regulator of insulin patients with metabolic syndrome.
and glucose metabolism [115]. Because of the latter action,
this agent might be useful in treatment of the metabolic Reduction of pro-thrombotic state
syndrome [116]. On the other hand, to date, telmisartin has
failed to show unique cardioprotection [117]. Caloric restriction and weight loss are accompanied by
reduction in coagulation activation factors [128]. At present
Management of hyperglycemia there are no specific drug therapies for a pro-thrombotic state
in patients with the metabolic syndrome other than aspirin.
Patients with metabolic syndrome commonly have predia- Aspirin can be recommended for patients with metabolic
betes, which consists of impaired fasting glucose, glucose syndrome who have ASCVD. The best recommendation for
intolerance, or hemoglobin A1C 5.7–6.4%. An important goal use of aspirin therapy in primary prevention is to follow
in these patients is to prevent the conversion to diabetes. current guidelines, which attempt to balance risk versus
There is a general consensus that the first goals of treatment benefit [129–131]. Generally, these guidelines favor use of
are weight loss of 10% of body weight and increasing physical aspirin for patients whose estimated 10-year risk for ASCVD
activity to at least 150 min/week of moderate activity [118]. is 410% provided there are no contraindications.
Lifestyle modification of this type will cut the rate of con-
version of prediabetes to diabetes in half [119]. Metformin refere nces
therapy likewise will slow conversion of prediabetes to
diabetes, but it is less effective than lifestyle therapy [119].
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