Metabolic syndrome: A new target of therapy?

Apply the definition of metabolic syndrome in practice.
Recognize the risk for cardiovascular disease and diabetes imposed by a diagnosis of metabolic syndrome.
Discuss the best approaches to the treatment of metabolic syndrome.

Metabolic syndrome (MetSyn) is a collection of major and emerging risk factors for atherosclerosis that tend to occur together. This syndrome has gone by various names, including Reaven's syndrome, the deadly quartet, syndrome X, insulin resistance syndrome, as well as metabolic syndrome. Because the natural history involves progression to atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes, or both, MetSyn is likely an important bridge between these 2 diseases.

The National Cholesterol Education Program (NCEP) has led an effort to educate physicians and patients about MetSyn. It is important to note that the NCEP crafted a highly practical definition for MetSyn that is easily remembered and integrated into clinical practice. Moreover, the NCEP incorporated MetSyn as a prominent element of the Adult Treatment Panel III (ATP III) guidelines for dyslipidemia.¹ Other consensus groups have adopted the ATP III definition.^2,3 MetSyn has sparked widespread interest because it is connected with 2 important conditions: atherosclerosis and insulin resistance.

A Case Study

Case history.

JR is a 54-year-old Mexican American woman who presented for a routine examination without complaints and with an unremarkable medical history. She is not a smoker, eats a typical Western diet, and has been doing aerobic exercise for several months. Her family history is notable for the sudden death of her father, who had diabetes, from a myocardial infarction (MI) at the age of 57 years. Her mother survived an MI at age 68, but died of a cerebrovascular accident in her mid-70s. Her brother has type 2 diabetes.

On presentation, JR's blood pressure (BP) was 132/88 mm Hg, and her pulse was 98 bpm. She stands 5 feet 4 inches and weighs 154 pounds (body mass index [BMI], 26.4 kg/m²), with a waist circumference of 36 inches. Her examination was unremarkable except for abdominal obesity. Fasting laboratory values were as follows: total cholesterol, 236 mg/dL; low-density lipoprotein (LDL) cholesterol, 152 mg/dL; high-density lipoprotein (HDL) cholesterol, 38 mg/dL; triglycerides, 232 mg/dL; and non-HDL cholesterol, 198 mg/dL. Her glucose level was 102 mg/dL, and her microalbumin/creatinine ratio was 40 mg/g. Her Framingham Risk Score (FRS) suggests a 2% chance of having an MI over the next 10 years. Since she was reaching the age at which her father died, she wanted to be aggressive with prevention.

Her physician counseled her on weight loss and referred her to a nutritionist and a personal trainer but did not initiate any drug therapy at this visit.

How is MetSyn diagnosed?

According to the ATP III guidelines, MetSyn is diagnosed when abnormal levels of any 3 of 5 parameters easily measured in clinical practice are present: waist circumference, triglycerides, HDL cholesterol, blood pressure, and fasting glucose (Table 1).¹ Although the routine use of emerging risk factors is generally discouraged by guidelines, MetSyn is a notable exception. Clinicians should broadly screen for MetSyn as part of the routine patient encounter, and all 5 clinical components should be checked.

Recently, a consensus group of leading researchers revisited the definition² and treatment ⁴ of MetSyn. The updated definition was endorsed by the American Heart Association (AHA), the National Heart, Lung, and Blood Institute (NHLBI), and the American Diabetes Association (ADA) (herein, the AHA/NHLBI/ADA panel), and expands on the ATP III guidelines by liberalizing the glucose criterion. The AHA/NHLBI/ADA panel replaced the older cutoff of fasting glucose ≥110 mg/dL with the new ADA cutoff for impaired fasting glucose (IFG) of ≥100 mg/dL.⁵ Furthermore, the glucose criterion now includes impaired glucose tolerance (IGT) on a 75-g oral glucose tolerance test (OGTT) as an alternative to IFG. The panel does not encourage use of the OGTT, however, because they doubt that its superior ability to predict ASCVD and type 2 diabetes outweighs the cost or inconvenience.²

This clinical definition of MetSyn is easy for clinicians to use, because it is limited to readily available parameters and the cutoffs are easy to remember. There are many other conditions associated with MetSyn, however, so it is worth mentioning that the clinical definition was conceived as a diagnostic tool rather than a comprehensive list of clinical abnormalities. Indeed, when it comes to treating MetSyn, the list swells to include additional components: insulin resistance, a prothrombotic state, and a proinflammatory state.

What causes MetSyn?

The etiology of MetSyn is likely multifactorial and touches upon multiple systems. Although the cause is not known, there are 3 important hypotheses: (1) obesity, (2) insulin resistance, and (3) independent factors.² The last category refers to genetic or biochemical mechanisms that drive the component conditions. Other factors may influence MetSyn, including advancing age, physical inactivity, hyperandrogenemia (eg, polycystic ovary disease), hypercorticoidism, and medications. Medications could lead to MetSyn through weight gain (eg, antidepressants, antihistamines, antipsychotics, or corticosteroids) or by directly influencing insulin resistance (eg, protease inhibitors for human immunodeficiency virus).⁴

Who Has MetSyn?

The Third National Health and Nutrition Examination Study (NHANES III) estimated the age-adjusted prevalence of MetSyn at 24%. The prevalence of MetSyn increases with age, such that only 7% of Americans in their 20s, but up to 44% of those in their 60s, have the condition.⁶ According to one researcher, a practical way to estimate prevalence is to simply deduct 20 from the age of the population of interest.⁷ A more detailed analysis from NHANES III found that the prevalence of MetSyn varies with gender and race; MetSyn was markedly increased in Mexican American women (27%), whereas the risk was lowest among African American men (14%).⁸

How common is ASCVD in patients with MetSyn?

NHANES III found a significant association between MetSyn and ASCVD, although ASCVD status was gauged by a self-reported history of prior events.⁹ Adjusting for age, sex, race, and smoking, subjects with MetSyn were twice as likely to have a past history of MI (odds ratio [OR], 2.01), cerebrovascular accident (CVA) (OR, 2.16), and MI/CVA (OR, 2.05). Three of the 5 ATP III diagnostic criteria for MetSyn were independently related to ASCVD: low HDL cholesterol, hypertriglyceridemia, and hypertension, as was insulin resistance (a required component of the World Health Organization diagnostic criteria). Because the method of detecting ASCVD was relatively insensitive in NHANES III, further studies to assess the prevalence of ASCVD in persons with MetSyn are necessary.

What is the prognosis of MetSyn?

There are ultimately 2 major prognoses of concern in MetSyn: (1) progression to ASCVD and (2) progression to type 2 diabetes. No prospective studies have been designed to test the strength of MetSyn as a risk factor for either ASCVD or type 2 diabetes. However, published retrospective analyses may be helpful for evaluating the prognosis. In general, more is known about the prognosis for ASCVD than progression to type 2 diabetes.

What is the risk for progression to ASCVD?

The incidence of ASCVD in those with MetSyn is not well known. Nevertheless, the ATP III report warns that the "metabolic syndrome and its associated risk factors have emerged as a coequal partner to cigarette smoking as contributors to premature CHD [coronary heart disease]."¹ A post hoc analysis from the Kuopio Ischaemic Heart Disease Risk Factor Study showed that men with MetSyn were about 3 to 4 times more likely to die of CHD than those without the condition (relative risk, 2.9-4.2) after adjustment for other major risk factors.¹⁰ This study supports the ATP III's contention that MetSyn identifies people whose risk exceeds that predicted by the major risk factors at any level of LDL cholesterol.

Comparable results were reported from a metaanalysis of several European trials, in which, depending on the definition, MetSyn raised the hazard ratio (HR) for CHD mortality between 1.7- to 2.3-fold for men and 1.6- to 2.8-fold for women, compared with those without MetSyn.¹¹ A secondary prevention trial reported a post hoc estimate of major CHD events and found that hyperlipidemic patients with MetSyn were more likely to have an event than patients without MetSyn (HR, 1.5).¹² Two primary prevention trials reported post hoc event rates for dyslipidemic patients with MetSyn, one finding an HR of 1.4 ¹² and the other an HR of 1.76 compared with subjects without MetSyn.¹³ Collectively, the post hoc studies of CHD events and mortality support the notion that MetSyn worsens the incidence of ASCVD.

What is the risk for progression to type 2 diabetes?

Often patients with MetSyn are more interested in the prognosis for developing type 2 diabetes than ASCVD. Patients with MetSyn and obesity or prediabetes have a greater risk of developing type 2 diabetes. The ADA defines prediabetes as either IFG (fasting glucose, 100-125 mg/dL) or IGT (2-hour OGTT with glucose 140-199 mg/dL).⁵ The West of Scotland Coronary Prevention Study (WOSCOPS) showed that patients without diabetes but with MetSyn were much more likely to develop type 2 diabetes (HR, 3.5) than those without MetSyn.¹³ Patients with 4 or 5 of the components of MetSyn were more than 24 times more likely to develop type 2 diabetes. A new analysis from the Framingham dataset showed that MetSyn was highly predictive of progression to type 2 diabetes in men and women, accounting for up to half of the type 2 diabetes risk in the study.¹

A follow-up visit.

JR returns 8 months later and reports that despite exercising twice a week and cutting back on unnecessary calories, she has not been able to lose weight. She has no new complaints. Her BP is 142/88 mm Hg, and her pulse is 102 bpm. She weighs 158 pounds, with a waist circumference of 36 inches (BMI, 27.1 kg/m²). Physical examination findings are unchanged. Fasting laboratory values were as follows: total cholesterol, 244 mg/dL; LDL cholesterol, 154 mg/dL; HDL cholesterol, 38 mg/dL; triglycerides, 258 mg/dL; and non-HDL cholesterol, 206 mg/dL. Her fasting glucose level was 108 mg/dL and her microalbumin/creatinine ratio was 60 mg/g.

Additional BP measurements confirmed a new diagnosis of mild hypertension, and an electrocardiogram showed left ventricular hypertrophy (LVH). Her FRS suggests that she has a 4% chance of having a major CHD event over 10 years (ie, CHD death or nonfatal MI).

Challenges for clinicians.

JR has all 5 clinical components of MetSyn yet her FRS is only 4%. 1. Are you confident that the ATP III guidelines give a fair appraisal of her ASCVD risk? ². Would you treat her hypertension with pharmacologic therapy? ³. Would you treat her atherogenic dyslipidemia with pharmacologic therapy? ⁴. Would you advise any other therapy? ⁵. Would you do any other tests to learn more about her ASCVD risk? What about her risk of developing type 2 diabetes?⁶. JR tells you that she heard an advertisement on the radio about electron-beam tomography (EBT). Her insurance does not cover it, but she tells you she would pay for it if you thought it would help reduce her risk. What do you tell her?

Clinical risk assessment for patients with MetSyn

The ATP III emphasizes risk assessment using the FRS, a clinical model for predicting the risk for ASCVD based on various major risk factors. Like other attempts to estimate ASCVD incidence, the FRS is based on a retrospective analysis. In practice, we are often confronted with patients who have many of the components of MetSyn, yet have a surprisingly low FRS. As clinicians, should we trust our clinical judgment or the FRS? In fact, we should trust both, and let the one inform the other. Indeed, we have also evaluated many patients who we thought had modest risk, but were surprised to find to be at high risk by the FRS. A working knowledge of the weaknesses of the FRS may help the clinician to compensate, just as the FRS may reveal weaknesses in our clinical judgment.

Editor's note:

Although we discussed general limitations of the Framingham dataset in the previous issue [ The first issue in this series, which appeared in April 2004, provided an overview of cardiovascular risk assessment], it is worth noting here that there are additional shortcomings that apply to MetSyn. First, the current FRS is based on a population of about 5000 patients examined between 1971 and 1974. The presumed causes of MetSyn involve risk factors that were less prevalent 30 years ago, especially obesity, prediabetes, and diabetes. It is probably not fair to expect this dataset to perform well for MetSyn, because it is unlikely to be representative of the current degree and mixture of risk factors. Second, although some components of MetSyn are emerging risk factors, the FRS includes only major risk factors, overlooking abdominal obesity, insulin resistance, hypertriglyceridemia, the proinflammatory state, and the prothrombotic state. Third, most of the women in the Framingham population were <50 years old, and few had ASCVD events. Fourth, racial differences in the prevalence of MetSyn may limit the accuracy of any model from a homogeneous population, such as the Framingham population. Finally, the FRS may underestimate ASCVD risk in insulin-resistant patients.² The AHA/NHLBI/ADA panel acknowledged a major need for improving ASCVD risk assessment in patients with MetSyn.⁴

Knowing these limitations can help to guide clinical decisions. For instance, it is good to know that a patient like JR, a prediabetic Mexican American woman with all 5 components of MetSyn, may have a low FRS because of a weakness in the model and not because she truly has negligible risk for ASCVD. Many patients are "outliers" compared with the rural 1970s Framingham population. Our clinical instincts often caution that many patients have greater risk than meets the eye. Simply checking an emerging risk factor could help the clinician confirm this suspicion and justify more aggressive prevention goals. Although the FRS is far from perfect, we strongly believe that it is the best tool for estimating ASCVD incidence. We initially base our risk assessment on the FRS and strengthen it with emerging risk factors when our clinical judgment disagrees with the FRS.

What is the optimal treatment of MetSyn?

The ATP III approach to MetSyn, summarized in Table 2, emphasizes therapeutic lifestyle changes to address the root causes: overweight/obesity and physical inactivity, as well as the associated insulin resistance. The supremacy of lifestyle modification hails from the belief that success with weight loss and exercise may stave off each of the other 4 clinical conditions of MetSyn. The ATP III notes, however, that "at present, most success in clinical practice comes from pharmacological modification of the associated risk factors."¹ The guidelines also state that improving atherogenic dyslipidemia, hypertension, and the prothrombotic state reduces risk for ASCVD.

What are the goals of treatment?

The ultimate goals of treatment for MetSyn are primarily to prevent ASCVD, and secondarily, to prevent the development of type 2 diabetes.

When possible, the clinician should select treatment for one goal that does not compromise the other. It is important that when a treatment for one outcome has the potential to compromise the other, ASCVD prevention takes precedence over type 2 diabetes prevention. For example, when a patient has a compelling clinical need for a thiazide diuretic or a beta blocker, the patient should not be denied these drugs for fear that they might hasten progression to type 2 diabetes. Preventing ASCVD is the priority because evidence for the benefit is solid; data for the untoward effects of these drugs on insulin resistance are still preliminary.

Treating obesity

Lifestyle changes.

The AHA/NHLBI/ADA panel defers to the evidence-based National Institutes of Health guideline on overweight and obesity.^2,14 A reasonable goal is weight loss of 7% to 10% from baseline in 6 to 12 months; this is more successful when accompanied by exercise. Ideally, all adults should strive for at least 30 minutes of moderate-intensity exercise on most days of the week.¹⁴ Nutrition counseling is also helpful when available. Large randomized clinical trials have shown that weight loss and exercise slow progression from prediabetes to type 2 diabetes.^15,16 Although there are no comparable data for progression to ASCVD, lifestyle modification improves the components of MetSyn.

Pharmacologic treatment.

Patients whose BMI exceeds 30 kg/m² may benefit from pharmacologic treatment of obesity as an adjunct to diet and exercise. This also applies to those with BMI ≥27 kg/m² with concomitant diseases (eg, hypertension, dyslipidemia, CHD, type 2 diabetes, obstructive sleep apnea).¹⁴ Orlistat and sibutramine are 2 commonly used antiobesity medications. Because sibutramine may raise BP, orlistat may have an advantage for patients with MetSyn. The Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study randomized more than 3000 patients without diabetes with BMI ≥30 kg/m² to lifestyle changes in addition to orlistat or placebo.¹⁷ Drug treatment of obesity reduced progression to type 2 diabetes almost 40% after 4 years ( = .003; number needed to treat [NNT], 35) compared with placebo. This benefit was only significant in patients who had IGT at baseline, however (relative risk reduction [RRR], 45%; NNT, 10).

Surgical treatment.

Patients with BMI ≥40 kg/m² (or ≥35 kg/m² with comorbid conditions) may benefit from surgical management of obesity when lifestyle modification or pharmacologic treatment fail.¹⁴ The Swedish Obese Subjects (SOS) study showed that gastric bypass led to a 20-kg weight loss after 8 years and reduced progression to type 2 diabetes by 81% compared with usual care ( = .0001; NNT, 7).¹⁸

Although JR meets the criteria for pharmacologic therapy (BMI ≥27 kg/m² with concomitant disease), she cannot afford to pay for this treatment out of pocket (her insurance does not reimburse for either obesity agent). She would prefer to continue improving her efforts at diet and exercise.

Treating insulin resistance

Lifestyle changes.

Vigorous weight loss and exercise improve insulin sensitivity, slowing progression from prediabetes to type 2 diabetes. The Diabetes Prevention Program (DPP) randomized patients with IFG or IGT to placebo, metformin, or intensive lifestyle changes (diet, weight loss, and exercise supported by an elaborate system of incentives to motivate patients). The intensive lifestyle strategy, which relied heavily on visits with nutritionists and other health professionals, reduced progression to type 2 diabetes about 60% over 3 years.¹⁵

This is remarkable because the reduction of type 2 diabetes with lifestyle changes was seen in patients who already had IGT, indicating severe insulin resistance. Such efforts might help patients with MetSyn lesser degrees of beta cell dysfunction. Therefore, as with obesity, lifestyle change is the cornerstone of treating insulin resistance.

It is not yet clear whether such a vigorous strategy will be practical on a population level, because the amount of resources employed by the lifestyle arm is not feasible for clinical practice. Nonetheless, experts support an aggressive approach based on lifestyle improvements.^1,3,4

Pharmacologic treatment.

Three medication classes retard the progression from prediabetes to type 2 diabetes, primarily by improving insulin resistance. The metformin arm of the DPP showed a 31% decrease in type 2 diabetes in 3 years compared with placebo.¹⁵ The Troglitazone in Prevention of Diabetes (TRIPOD) study randomized Hispanic women with a history of gestational diabetes to troglitazone or placebo for 2.5 years.¹⁹ Troglitazone reduced progression to type 2 diabetes by 55%. The Study to Prevent Non—Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) randomized patients to acarbose or placebo for 3.3 years.²⁰ Acarbose reduced progression to type 2 diabetes by 25%. Acarbose also cut ASCVD events in half ( = .03; NNT, 40), and cut new-onset hypertension by one third ( = .006; NNT, 19).²¹ The apparent improvements in ASCVD and hypertension give credence to the idea that insulin resistance and ASCVD are connected and hint that pharmacologic treatment of insulin resistance could improve ASCVD, at least in patients with prediabetes.

Although drug therapy for insulin resistance is likely safe and efficacious for preventing type 2 diabetes, no medications are approved for patients without diabetes. The AHA/NHLBI/ADA panel recommended against insulin sensitizers for ASCVD prevention, pointing out that neither metformin nor thiazolidinediones have been shown to reduce ASCVD events.⁴ The ADA has decided against recommending medical treatment to prevent type 2 diabetes, given that no studies have shown that treating patients with prediabetes prevents the complications of diabetes and its cost effectiveness has not been ascertained.²²

During the discussion of her risk for type 2 diabetes, JR recalls that during her last pregnancy she had gestational diabetes, which resolved. She also has first-degree relatives who have type 2 diabetes. Her physician ordered a 2-hour OGTT to rule out type 2 diabetes; the glucose level was 106 mg/dL fasting and rose to 196 mg/dL 2 hours after a 75-g load of glucose.

Although this test shows that she does not currently have type 2 diabetes, it confirms that she has IGT in addition to IFG. There are multiple medications that might safely prevent progression from IGT to type 2 diabetes, but none are approved for patients without diabetes. Experts do not recommend such treatment at this time, because it has not been proved that they are cost effective or reduce ASCVD or other diabetic complications. The OGTT suggests a high likelihood of progression to type 2 diabetes, and JR and her physician agree to monitor her condition with periodic laboratory tests.

Treating atherogenic dyslipidemia

Atherogenic dyslipidemia in patients with MetSyn is defined by elevated triglycerides (≥150 mg/dL), low HDL cholesterol (<40 mg/dL in men; <50 mg/dL in women), and small, dense LDL cholesterol (although the ATP III recommends against routinely measuring the latter). The ATP III makes the following ranked recommendations for patients with MetSyn with atherogenic dyslipidemia:

Treat LDL cholesterol first
For those patients with triglycerides ≥200 mg/dL, calculate the non-HDL cholesterol level non-HDL cholesterol = total cholesterol — HDL cholesterol non-HDL cholesterol goal = LDL cholesterol goal + 30 mg/dL

Lowering LDL cholesterol is imperative because LDL lowering is proven to reduce ASCVD events. There is far less evidence to support lowering non-HDL cholesterol as a means of ASCVD prevention. According to the ATP III, "the presence of the metabolic syndrome provides the option to intensify LDL-lowering therapy after LDL cholesterol goals are set with the major risk factors."¹ In practice, however, it is sometimes difficult to monitor LDL cholesterol, because in patients with triglycerides >400 mg/dL, the LDL cholesterol cannot be accurately calculated. In this case, we suggest directly measuring the LDL cholesterol.

Treatment of either goal begins with lifestyle changes, especially weight loss and physical activity. Because achieving the LDL cholesterol goal is the priority, patients who don't reach their goal with weight loss and exercise usually require treatment with a statin.

After the LDL goal is met, the non-HDL cholesterol becomes a target for additional therapy. If the non-HDL cholesterol remains elevated despite LDL cholesterol below goal, the ATP III suggests either increasing the dose of the statin or combination therapy. For combination therapy, they advocate pairing a moderate dose of a statin with a triglyceride-lowering drug (niacin or fibrate).¹ Figure 1 shows the effect of different drug classes on HDL cholesterol and triglycerides.

HMG-CoA reductase inhibitors (statins).

The initial decision to implement pharmacologic treatment for patients with elevated triglycerides and low HDL cholesterol levels depends primarily on the LDL cholesterol level. Barring very high triglycerides (eg, >400 mg/dL), a patient who is not at the LDL cholesterol or non-HDL cholesterol goal will generally benefit from a statin as first-line therapy. Many landmark clinical trials have shown that statins decrease CHD risk by about one third. However, statins have comparatively weak effects on the HDL—triglyceride axis, increasing HDL cholesterol levels by only 5% to 10%, while lowering triglycerides by 7% to 30%.¹

Since no prospective studies intentionally enrolled patients with MetSyn, the benefit of statin treatment in this population is unknown. Moreover, most trials excluded patients with triglycerides >400 mg/dL, making it even harder to gauge benefits. Post hoc analyses from lipid trials give conflicting results regarding ASCVD prevention in patients with MetSyn. The Heart Protection Study found that a subgroup with triglycerides >354 mg/dL benefited less from statin therapy,²³ and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) failed to document a benefit from statin therapy in patients with MetSyn.²⁴ A subgroup of the Scandinavian Simvastatin Survival Study (4S) with high LDL cholesterol and atherogenic dyslipidemia benefited more from the statin compared with those with an isolated elevation of LDL cholesterol. High LDL cholesterol is not typical for MetSyn, however.²⁵ Statins also differ somewhat in their ability to raise HDL cholesterol and lower non-HDL cholesterol (ie, LDL cholesterol and triglycerides) (Figure 2).

Fibric acid derivatives (fibrates).

The fibrates (clofibrate, ciprofibrate, bezafibrate, gemfibrozil, and fenofibrate) lower triglyceride levels very effectively, by between 25% and 50%, and raise HDL cholesterol by 10% to 20%.¹ Fibrates are more effective at raising HDL cholesterol levels when triglyceride levels are elevated. The Helsinki Heart Study, which enrolled men with non-HDL cholesterol >200 mg/dL who were free of CHD at baseline, showed a reduction in CHD events with gemfibrozil compared with placebo.²⁶ Part of this benefit was credited to a modest increase in HDL cholesterol levels.²⁷

The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) enrolled patients with low HDL cholesterol and low LDL cholesterol levels and showed that gemfibrozil reduced CHD events compared with placebo.²⁸ In part, the benefit was attributed to a modest increase in HDL cholesterol levels, rather than reduction of triglycerides.²⁹ This was the first study to suggest that improving HDL cholesterol or triglycerides rather than lowering LDL cholesterol could lower the risk of CHD events.

Because fibrates are well tolerated and improve atherogenic dyslipidemia, we often add a fibrate to statin therapy. Patients must be carefully monitored, however, because use of a statin with a fibrate, particularly gemfibrozil, increases the risk of myopathy.

Nicotinic acid (niacin).

Niacin is currently the most effective drug for raising HDL cholesterol levels (15%-35%), and it also lowers triglycerides effectively (20%-40%).¹ A secondary prevention trial, the Coronary Drug Project, found a significant reduction in CHD events with niacin.³⁰ Patients with triglycerides ≥150 mg/dL had a similar reduction in events to those with triglycerides <150 mg/dL.

We frequently add niacin to a statin in patients with MetSyn because of the salutary effects on atherogenic dyslipidemia. Niacin has been associated with insulin resistance, however, and some diabetic patients taking niacin have a rise in glucose requiring an increase of hypoglycemic treatment.³¹ The hyperglycemic effect is more likely in patients with diabetes than patients without diabetes, and the clinical significance in patients without diabetes is debatable.³² Nevertheless, because of the potential for worsening insulin resistance, we are less likely to treat patients with MetSyn and borderline type 2 diabetes with niacin, unless ASCVD prevention would be hampered without its use.

Because JR has 2 major risk factors, her physician believes that she has an intermediate risk of having a CHD event (CHD death or nonfatal MI) in the next 10 years and sets the following goals:

Lower her LDL cholesterol to <130 mg/dL.
Once the LDL cholesterol is below goal, try to lower her non-HDL cholesterol to <160 mg/dL.

She started taking a moderate dose of a statin, which lowered her LDL cholesterol to 125 mg/dL, but her non-HDL cholesterol remained above goal at 180 mg/dL. Adding fenofibrate brought her non-HDL cholesterol below goal.

Treating elevated BP

MetSyn often presents with either prehypertension or stage 1 hypertension and should be treated initially with lifestyle modification.3 If BP remains above 140/90 mm Hg, antihypertensive medication is warranted. Although there are no prospective studies in the MetSyn population, current hypertension and lipid guidelines reflect a belief that the particular drug taken probably makes little difference with respect to progression toward ASCVD, as long as it lowers BP.^1,3 The variety of antihypertensive options may allow the clinician to select drugs that reduce progression to ASCVD without accelerating progression to type 2 diabetes.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) studied hypertensive patients older than 55 years who had at least 1 other ASCVD risk factor.³³ Patients were treated with antihypertensive regimens based on a thiazide diuretic, a calcium channel blocker (CCB), or an angiotensin-converting enzyme (ACE) inhibitor.

After 5 years, there was no significant difference in the primary outcome (CHD death or nonfatal MI) or all-cause mortality. However, the group taking a thiazide was much more likely to develop type 2 diabetes, suggesting that the other drug strategies may have an advantage in insulin-resistant populations. The ACE inhibitor group was about 40% less likely to develop type 2 diabetes than those taking a thiazide ( <.001), suggesting that favoring the ACE inhibitor in 23 patients would prevent 1 case of type 2 diabetes (ie, NNT, 23). Although the differences were not as impressive, the group assigned to the CCB was also less prone to develop type 2 diabetes than those taking a thiazide (RRR, 15%; NNT, 57; = .04).

Exploratory findings from some antihypertensive trials suggest that certain drugs, particularly ACE inhibitors, or angiotensin receptor blockers (ARBs), may slow or prevent progression to type 2 diabetes in the hypertensive population.^34-37 Treatment centered around these drugs may have an advantage over thiazides ^33,38 or beta blockers,^38,39 drugs that worsen insulin resistance. A recent hypertension trial showed that use of low-dose thiazides was associated with development of type 2 diabetes, and that the subgroup with new-onset type 2 diabetes, in turn, had more ASCVD events.⁴⁰ This finding makes it hard to dismiss these diabetogenic effects and highlights the need for further study with prospective randomized controlled trials. Indeed, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial will prospectively evaluate the ability of ACE inhibitor treatment to slow progression to diabetes.

Because there are so many antihypertensives to choose from, clinicians are in a position to select first-line drugs that could reduce the risk of both ASCVD and type 2 diabetes in patients with MetSyn. This is probably not nearly as important in "classic" hypertension, where more severe disease requires multiple drugs anyway. However, patients with MetSyn often present with milder forms of hypertension,³ so the influence of the first-line drug may have more weight than in more aggressive forms of hypertension. When treating patients with MetSyn, we prefer drugs, such as ACE inhibitors, ARBs, or CCBs, that are unlikely to worsen insulin resistance as our first- and second-line antihypertensives. We do not, however, avoid using diuretics or beta blockers when needed, because the evidence for overall ASCVD benefit from these drugs is solid.

JR's physician decided to treat her hypertension with an ACE inhibitor, because this class may especially benefit those with LVH and microalbuminuria. In addition, an ACE inhibitor may be less likely than other antihypertensives to worsen her prediabetes.

Treating the prothrombotic state

Patients with MetSyn are assumed to have a prothrombotic state, so it is not necessary to order additional laboratory tests to prove this.⁴ There are no trials in the MetSyn population, but the ATP III and the AHA/NHLBI/ADA panel endorsed the use of aspirin for patients with MetSyn who have moderate or high risk for ASCVD.^1,4 Therapy is usually reserved for those whose 10-year FRS for CHD is ≥10%, in accordance with AHA recommendations.⁴¹ In practice, we rarely advise aspirin therapy for patients younger than age 40 years, unless they have unusually high risk or already have ASCVD.

Because JR's FRS is well below 10%, a strict reading of the guidelines discourages the use of aspirin. However, JR's physician believed that she had moderate risk based on multiple major and emerging risk factors. After he discussed the uncertainty of the available evidence and covered potential risks and benefits with her, JR elected to start taking an 81-mg aspirin daily.

Treating the proinflammatory state

Inflammation, Metabolic Syndrome, and CV Risk Reduction

Although a low-grade inflammatory state is a component of MetSyn, the ATP III did not find sufficient evidence to endorse the routine use of inflammatory markers in assessing risk.¹ An upcoming issue of will be dedicated to exploring the connection between inflammation and ASCVD risk. The best clinical marker of low-grade inflammation is high-sensitivity C-reactive protein (hs-CRP), and an hs-CRP level ≥3 mg/L is also an independent risk factor for ASCVD.⁴² Patients whose hs-CRP is persistently ≥3 mg/L may benefit from more aggressive preventive therapy. Like the use of many emerging risk factors, this practice is optional based on clinical judgment and is not recommended for routine use.

We do not check hs-CRP in every patient. However, in patients with MetSyn and an FRS <20%, we believe this test can be useful. The Framingham dataset apparently underestimates risk in insulin-resistant patients, such as those with diabetes; we suspect this extends to patients with MetSyn. Furthermore, the FRS is a weak predictor of ASCVD in women, as they are not well represented in the original cohort. The hs-CRP test and other emerging risk factors help the clinician compensate for this weakness. If the hs-CRP level is ≥3 mg/L, we might manage patients with an FRS between 10% and 20% as if they had a CHD risk equivalent. In addition, we sometimes use an elevated hs-CRP to upgrade patients with MetSyn with an FRS <10%, treating them as if they had intermediate ASCVD risk. This might prompt us to initiate aspirin therapy or a statin.

No prospective trials have yet shown that this approach reduces events. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) may help to settle this issue. This ongoing trial enrolls subjects without CHD who have hs-CRP >2 mg/dL and LDL <130 mg/dL and randomizes them to treatment with either rosuvastatin or placebo. The criteria will likely lead to the enrollment of many patients with MetSyn.

JR's physician believes that she has several risk factors for ASCVD that are not reflected in the clinical guidelines and is considering invoking the ATP III option of intensifying LDL cholesterol treatment. He decides to test her for hs-CRP, and, if this is positive, he will intensify therapy to pursue a goal of LDL cholesterol <100 mg/dL.

In response to JR's inquiry about EBT, her physician advises her to readdress the issue when the results of the hs-CRP test are available. Elevated hs-CRP levels might obviate the need for EBT as an ASCVD screening tool.

We will revisit JR in the next article in this series, which will focus on emerging inflammatory markers of ASCVD risk.

Conclusion

Much about MetSyn remains a mystery. In contrast to other emerging risk factors, clinicians should screen for MetSyn as part of the routine clinical encounter. Although exploratory evidence supports MetSyn as an important risk factor for ASCVD and type 2 diabetes, prospective studies on the incidence of these outcomes and the efficacy of treatment are needed. Nonetheless, current guidelines suggest that MetSyn augments the risk associated with major risk factors and should figure prominently in efforts to prevent ASCVD and type 2 diabetes. Currently, the most important treatments for patients with MetSyn include therapeutic lifestyle changes and treatment of dyslipidemia, hypertension, and the prothrombotic state.

Circulation.

1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. 2002;106:3143-3421.

Arterioscler Thromb Vasc Biol.

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Hypertension.

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