Articles  |   March 2010
Treating risk components of the metabolic syndrome
Article Information
Cardiovascular Disorders / Endocrinology / Hypertension/Kidney Disease / Preventive Medicine / Professional Issues / Diabetes
Articles   |   March 2010
Treating risk components of the metabolic syndrome
The Journal of the American Osteopathic Association, March 2010, Vol. 110, eS6-eS13. doi:
The Journal of the American Osteopathic Association, March 2010, Vol. 110, eS6-eS13. doi:
The metabolic syndrome constitutes a cluster of risk factors for incident cardiovascular disease (CVD) and type 2 diabetes mellitus. These risk factors occur together more often than singly by chance, and different organizations have developed varied criteria defining this syndrome. 
In a joint statement, the International Diabetes Federation Task Force on Epidemiology and Prevention, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity recently attempted to unify their differing criteria.1 The risk factors common to all definitions were: 
  • elevated blood pressure (BP)
  • elevated glucose and triglyceride (TG) levels
  • reduced high-density lipoprotein cholesterol (HDL-C)
  • central obesity.
The panel recommended that waist circumference be considered a criterion rather than an obligatory component of metabolic syndrome as previously defined by the International Diabetes Federation. A single set of cut-points would be used for all components except waist circumference, where national or regional criteria may be used until further research helps to reach consensus (Table 1). 
Table 1
Diagnostic Criteria for Metabolic Syndrome
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Table 1
Diagnostic Criteria for Metabolic Syndrome
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The 2009 Canadian Cardiovascular Society guidelines published updated criteria for the metabolic syndrome that included waist circumference with similar national criteria as noted above, but differed from the joint statement by considering waist circumference an obligatory component of the syndrome, along with at least two other defining risk factors.2 
Individuals diagnosed with the metabolic syndrome, defined by the presence of at least three of the five risk factors, have approximately twice the risk for developing cardiovascular disease over the next five to 10 years as similar individuals without the syndrome.1,3 
A continuum of risk is noted as the number of risk factors increases to four or five, and risk is further augmented if the syndrome persists over a longer time.1,3,4 Our discussion of the treatment of metabolic syndrome risk factors will focus on the five risk factors shared by all these analyses and the therapeutic effect of each risk factor on overall cardiovascular risk. 
Elevated fasting blood glucose
By definition, the presence of diabetes is a criterion for metabolic syndrome. Diagnostic criteria for prediabetes include impaired fasting blood glucose, impaired glucose tolerance, and metabolic syndrome.5 The presence of at least two prediabetes criteria renders an individual at increased risk for type 2 diabetes, and when impaired fasting glucose is one of the criteria for a diagnosis of metabolic syndrome, the risk for diabetes is even stronger. In fact, metabolic syndrome is a stronger predictor of incident type 2 diabetes mellitus than of incident coronary heart disease (CHD).6 
The recommended treatment goals for prediabetes are similar to those for impaired fasting glucose as a component of metabolic syndrome: glycemic control and control of cardiovascular risk factors. In patients diagnosed with metabolic syndrome who have impaired fasting glucose, therapy is based on intensive lifestyle modification, especially weight reduction and increased physical activity, which can delay progression to type 2 diabetes.6 
Although glycemic control has been shown to lower risk of microvascular events, the effect of intensive glycemic control on cardiovascular events is less clear.7 Three recent, large, randomized trials—ADVANCE, ACCORD, VADT—utilized the full spectrum of diabetic medications. Many of the trial participants had metabolic syndrome, intensive glycemic control—achieved A1c <7% (6.4% in ACCORD and ADVANCE; 6.9% in VADT)—that did not result in a significant reduction of cardiovascular events.8-10. 
Overall, mortality increased in ACCORD, which resulted in early termination of the trial, creating a concern that the risks associated with intensive glycemic control, such as hypoglycemia, may outweigh the benefits, especially in the elderly or those who had a longer duration of diabetes or advanced atherosclerosis. 
Current evidence suggests that the best way to protect patients with type 2 diabetes and, by inference, those with impaired fasting glucose, against cardiovascular disease is to target all CHD risk factors, including those associated with the metabolic syndrome. 
There is no compelling evidence that the pharmacologic lowering of glucose has a significant benefit on lowering cardiovascular events in patients with impaired fasting glucose as a component of the metabolic syndrome. 
When lifestyle modification fails to improve impaired fasting glucose levels, especially in high-risk individuals, pharmacologic intervention with metformin and/or acarbose has been a suggested option, but the evidence basis for this strategy has not yet been established.5 Treatment of CVD with thiazolidinediones have been debated, with potential differences noted between rosiglitazone (neutral to negative beneficial effect) and pioglitazone (neutral to positive beneficial effect).11-13 Until more definitive studies are conducted, the thiazolidinediones, especially rosiglitazone, should be avoided as an agent for treating CVD. 
Elevated blood pressure
By definition, the presence of hypertension constitutes one criteria for metabolic syndrome. Pre-hypertension is designated as either systolic blood pressure of 120-139 mm Hg or diastolic 80-89 mm Hg.14 As noted previously, blood pressure criteria for metabolic syndrome also includes individuals who are pre-hypertensive for which current guidelines emphasize lifestyle modification as the first-line strategy. 
When an individual with the metabolic syndrome has a blood pressure that meets criteria for hypertension, drug therapy may be considered according to the current JNC 7 guidelines akin to those recommendations for diabetics or chronic renal disease patients, such that a reduction to <130/80 mm Hg is recommended. 
A recent evaluation of the Framingham Heart Study found that hypertension was the risk factor most often associated with the diagnosis of metabolic syndrome.15 This supports prior National Health and Nutrition Examination Survey (NHANES) data indicating that elevated blood pressure was the most common component of metabolic syndrome in men and third most common in women.16 
In the World Health Organization (WHO) definition of metabolic syndrome, insulin resistance is considered an obligatory criterion. Because metabolic syndrome markedly increases the risk for incident diabetes, it may be considered a compelling indication for antihypertensive medications designated for diabetes, such as angiotension-converting enzyme inhibitors (ACE-Is) and angiotensin II-AT1 receptor blockers (ARBs).17 An additional advantage of ACE-Is and ARBs is their favorable effect on metabolic risk factors and incident diabetes, but no data are available yet on their CV outcomes compared with those of beta-blockers and diuretics.18 
In the GOOD trial, individuals with metabolic syndrome and hypertension who had dyslipidemia rather than impaired glucose tolerance were more likely to exhibit resistance to antihypertensive medications.19 In a recent analysis of the ADVANCE trial, when blood pressure control was attained, intensive blood glucose control was associated with an additional 10% reduction (P=.013) in primary events, suggesting the combined benefits from blood pressure and glucose control enhanced the benefits noted by each individually.20 
In the INVEST trial, combination therapies with verapamil/trandolapril and atenolol/hydrochlorothiazide were equivalent in preventing death, myocardial infarction (MI), and stroke; however, when BP was lowered below 119/84 mm Hg, this benefit eroded and was replaced with an increasing risk for MI and all-cause death.21 In the CAMELOT trial, patients with coronary artery disease (CAD) and normal BP (mean 129/78 mm Hg) were randomized to either amlodipine 10 mg, enalapril 10 mg or placebo.22 
Amlodipine significantly reduced cardiovascular events and enalapril trended to do the same, each by further decreasing BP 5/2.5 mm Hg. Data from INVEST and CAMELOT suggest that the optimal systolic BP in CAD is less than 140 mm Hg and in the range of 120 mm Hg, while lowering below this level may result in an increase in CV events. 
Currently there is no consensus on which antihypertensive therapy should be used to treat patients with the metabolic syndrome, and it remains unclear whether tight blood pressure control outweighs the potential adverse risks from a lower perfusion pressure. As with impaired fasting glucose, treatment of the other abnormal components of the metabolic syndrome appear equally important in the overall reduction of CV events in those with the hypertension component. 
Increased waist circumference
In every definition of the metabolic syndrome, central obesity, manifested by increased waist circumference, is a key component. Lifestyle therapies that include physical activity of 30 to 60 minutes of moderate intensity at least five days per week, alcohol moderation, reduced consumption of saturated fats, trans fats, cholesterol control and increased consumption of fruits and vegetables offer the first-line strategy for managing metabolic syndrome from the perspective of weight as well as prehypertension and prediabetes.23 
Eating plans involving very low carbohydrate and/or very low fat—such as the Atkins, Zone, Sugar Busters, and South Beach diets—have resulted in short-term weight loss but did not show an associated reduction in CV events. Similarly, medications for weight loss, such as sibutramine, diethylpropion, orlistat, bupropion, topiramate and phentermine, have been shown to produce modest weight loss but not yet to reduce cardiovascular events.24 
To further complicate the issue of weight changes associated with the metabolic syndrome and CV events, data from coronary intervention studies are somewhat paradoxical; major cardiovascular events in individuals undergoing coronary revascularization procedures have demonstrated an increase at both extremes of weight (ie, body mass index [BMI] <18.5 kg/m2 and BMI >35 kg/m2).25 In addition, approximately 20% of obese individuals have normal metabolic profiles and appear to represent a much lower risk for CV events than average or normal weight individuals with the metabolic syndrome. 
Current recommendations and goals for individuals with increased waist circumference are to reduce weight by 7% to 10% during the first year, with continued weight loss thereafter, and to ultimately achieve a desirable weight with a BMI <25 kg/m2.17 No specific diet is recommended for weight reduction; however, the DASH diet for blood pressure, the NCEP-ATP III diet for dyslipidemia, and the Mediterranean diet for CVD prevention are often recommended. None of these diets have been shown to combine weight loss with CV event reduction.26 Bariatric surgery has been shown to result in significant weight loss in morbidly obese patients, with a resultant decrease in MI and CV mortality.27 
Elevated triglyceride levels
Although elevated triglyceride levels and decreased HDL-C are the two lipids considered risk factors in the metabolic syndrome, only elevated triglyceride triggers the NCEP-ATP III guidelines for the secondary target of non-HDL-C.28 The non-HDL-C target is enacted when the low-density lipoprotein cholesterol (LDL-C) goal is achieved, yet the triglyceride levels persist above 200 mg/dL, resulting in a recommendation to intensify lifestyle therapy or add drug therapy to attain the appropriate non-HDL-C goal of 30 mg/dL above the LDL-C goal. 
Despite a strong epidemiologic association between triglyceride levels and CVD, the evidence becomes less clear when corrected for HDL-C, total cholesterol (TC), LDL-C and a non-fasting state. 
A recent analysis of the Emerging Risk Factors Collaboration reviewed 302,430 individuals without vascular disease from 68 long-term prospective studies.29 In contrast to previous findings based on much less data, this analysis concluded that triglyceride levels were not independently associated with CHD risk, after adjusting for HDL-C and non-HDL-C. The inability of triglyceride levels to predict CHD events also persisted in women and non-fasting states. 
From this analysis, triglyceride measurement provided no additional information on vascular risk if HDL-C and TC levels were measured. However, this analysis did not explore the value of changing triglyceride levels over time and resultant CHD risk. The MELANY trial evaluated 13,553 men aged 15 to 35 years who had repeat triglyceride levels after five years.30 Compared with subjects whose baseline and follow-up triglycerides were <80 mg/dL, those with values >131 mg/dL had a hazard ratio of 8.23 for CHD. Increases in triglyceride over five years correlated with increasing BMI and decreasing exercise and could be construed as a surrogate for the metabolic syndrome. 
The evidence for lowering triglyceride levels and reducing CV events is not extensive, and the current guidelines do not define goals for TG lowering but rather utilize non-HDL-C. 
In the PROVE-IT trial in patients with acute coronary syndrome (ACS) treated with either pravastatin or atorvastatin, for each 10 mg/dL decrease of triglycerides, the incidence of death, MI, or recurrent ACS was lowered by 1.6% after adjustment for LDL-C, non-HDL-C, and HDL-C.31 
Those who achieved the triple goal of lowering LDL-C <70 mg/dL, C-reactive protein (CRP) < 2 mg/L, and triglycerides <150 mg/dL had a better outcome than those who achieved just the LDL-C and CRP goals. It is not known whether similar benefits could be attained in a non-ACS population or could be extrapolated to other medications that may be more effective in lowering triglyceride levels. Because almost all interventions lowering triglyceride levels also affect HDL-C and LDL-C, it has been very difficult to determine any benefit from reducing triglyceride levels independent of simultaneous changes in LDL-C and HDL-C. 
Decreased HDL-C level
Because HDL-C elevation is frequently related to triglyceride lowering, it has been difficult to differentiate these as individual risk parameters, and, therefore, these two lipids have been frequently linked as metabolic dyslipidemia. The combining of TG and HDL has been explored as the TG/HDL ratio. In the MESYAS study, the TG/HDL ratio was used as a surrogate marker for insulin resistance and a marker for incident CHD across all categories of BMI.32,33 
HDL-C has been proposed as a tertiary target once the LDL-C and non-HDL goals have been met.14 Raising HDL-C by lifestyle change or medication independent of the other lipid variables, especially LDL-C, however, has not been shown to reduce CV events. Therefore, the current NCEP guidelines do not include specific goals for raising HDL-C. The Emerging Risk Factors Collaboration did confirm HDL-C as an independent predictor of CHD risk and suggested a 65% decrease in incident CVD when combining a 15 mg/dL increase in HDL-C with an 80 mg/dL decrease in non-HDL.29 
A major issue with HDL-C, as with triglycerides, is that a change in lifestyle or medications, independent of other lipid changes, is generally not robust. The literature suggesting a CHD benefit is not extensive. A study of intensive lifestyle changes in obese metabolic syndrome patients showed a modest decrease in weight and decreases in triglycerides and LDL-C, but a decrease in HDL-C, albeit the inflammatory index from HDL also decreased.34 
A recent meta-analysis of 108 HDL-C trials (140,890 patients) treated with lipid-modifying agents found no significant association with HDL-C change for CV events, when adjusted for LDL-C.35 To further confound the HDL-C issue, the trials in which the largest HDL-C increases were noted with the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, resulted in either neutral or negative effects. Thus, in some studies, HDL-C was increased with negative CV effects, while in other studies, it resulted in improvement of metabolic risk factors such as weight and triglyceride levels but with a concomitant decrease in HDL-C. 
Clearly the HDL-C story is more complicated than most, if not all, of the other lipid and metabolic risk factors. To date, no compelling evidence demonstrates that isolated raising of HDL-C in individuals with the metabolic syndrome has a beneficial effect on CV outcomes. 
Combined risk factor intervention
Because the diagnosis of metabolic syndrome requires the presence of only three of the five risk factors, many combinations will lead to that diagnosis. The Framingham Heart Study indicated that two combinations of risk factors appeared to have a higher risk profile that more than doubled the risk for cardiovascular disease and mortality. The group with central obesity, high blood pressure and hyperglycemia had the highest risk of incident cardiovascular disease (2.36-fold) and mortality (3-fold) followed by the group with dyslipidemia (increased TG, decreased HDL) and elevated blood pressure (1.94 CVD; 2.73 mortality).15 
These data are consistent with previously published epidemiologic studies that indicated that hypertension was the predominant risk factor driving the increased CVD risk associated with the metabolic syndrome.23 Therefore, the contribution of the various metabolic risk factors individually and collectively may be unbalanced and require further definition of this syndrome before determining cardiovascular risk and requisite therapeutic goals. 
Therapeutic outcome trials addressing the individual parameters of metabolic syndrome as a collective group do not exist as such. The Steno 2 Trial came closest to evaluating a comprehensive approach to the risk for CVD from metabolic syndrome.36 
Steno 2 was a type 2 diabetes trial, in which 30% of participants had known CVD. And, since NHANES data suggested that 87% of type 2 diabetics have the metabolic syndrome, this trial was a reasonable surrogate for a comprehensive therapeutic approach to metabolic syndrome.37 The diabetes trial demonstrated a prespecified treatment regime for aggressively treating three metabolic risk factors (glucose, blood pressure and triglycerides) to goals of A1c < 6.5%, SBP <130 mm Hg, and triglycerides <150 mg/dL, as well as lowering total cholesterol to <175 mg/dL and decreasing the number of smokers. 
Although not a primary aim, the HDL-C increased from 40 mg/dL to 51 mg/dL; however, both BMI and waist circumference actually increased slightly over the study period. The results in Steno 2 revealed a significant 46% decrease in overall mortality and significant 57% decrease in cardiovascular mortality over a 13-year, extended follow-up period. 
The Steno 2 trial represents the benefit of aggressive treatment of multiple risk factors in diabetics, most of whom had the metabolic syndrome. Besides lowering LDL-C to 71 mg/dL in those intensively treated versus 77 mg/dL in those conventionally treated, additional improvements were noted in four of the five metabolic criteria (FBG, BP, TG, HDL); however, the fifth criterion, waist circumference, actually increased in both men and women. 
Two other trials also evaluated a more comprehensive approach to the treatment of cardiovascular events in patients with stable coronary heart disease, the COURAGE and BARI-2D studies.38,39 
In COURAGE, 2,297 patients with stable coronary disease were randomized to optimal medical therapy with or without revascularization. Optimal medical therapy consisted of anti-platelet, anti-ischemic secondary prevention with ACE-Is or ARBs and lipid therapy targeting LDL-C, HDL-C and TG. 
Although not specifically delineated as having the metabolic syndrome, many patients had multiple metabolic risk factors, eg, 32% were diabetic and 66% hypertensive, and therefore represented a high-risk metabolic cohort. Although weight was minimally increased and A1c levels were unchanged, there was a benefit in the other metabolic risk factors, in addition to LDL-C, which resulted in a cumulative rate of CV events in the range of 20% over 4.6 years. 
When COURAGE results were compared with five-year event rates from the Cholesterol Treatment Trialists' (CTT) Collaborators that reviewed 90,056 participants in 14 statin trials, the five-year major event rate was 25% in controls and 22% with a statin. These results suggest a possible additional improvement with a multi-faceted approach, even though two metabolic factors, weight and A1c, were unaffected.40 
The BARI-2D trial evaluated a multi-faceted approach in stable coronary patients with diabetes. Although only 28.5% achieved the goals of an A1c <7%, BP <130/80, and LDL <100 mg/dL, the major CV event rate ranged from 20% to 25%. This was lower than the sub-analysis of 18,686 diabetics from the CTT collaborators in which CV events ranged from 30% to 35% over 4.3 years.41 Both COURAGE and BARI-2D evaluated individuals in higher risk groups and supported the multirisk factor approach espoused in the Steno 2 Trial. 
To summarize, the above analyses suggest that as independent variables, the evidence does not support a clinically significant benefit in the reduction of CV disease by targeting a single component of the five metabolic risk factors. There is no strong evidence base that incident CVD can be prevented by treating the isolated risk factors of impaired fasting glucose, prehypertension, increased waist circumference, elevated triglycerides, or low HDL-C with medications. So what are we to do? The metabolic syndrome is a composite of these factors that requires a multifocused approach to improve all the abnormal risk components. However, this strategy also includes at least one other variable that is not part of the syndrome, LDL-C. 
Treating LDL-C in the metabolic syndrome
Both secondary and primary prevention trials showed that lowering LDL-C with a statin reduced the risk of CV events in individuals with metabolic syndrome.42,43 
The Cholesterol Treatment Trialists' (CTT) collaborators' meta-analysis revealed that statin therapy equally benefitted individuals whether they were diabetic or not, and this benefit was independent of their weight, blood pressure, blood glucose, triglyceride level or HDL-C level. So one could surmise that statin therapy should benefit individuals independent of their metabolic status.40,41 This premise was confirmed in the JUPITER trial where 17,802 healthy men and women, of whom 6,375 (41%) had the metabolic syndrome with a baseline LDL-C <130 mg/dL, were randomized to rosuvastatin 20 mg or placebo.44 
In JUPITER, a significant reduction in vascular events was seen in those with and without the metabolic syndrome, confirming the benefit of statin treatment in lowering LDL-C in patients with metabolic syndrome. The JUPITER trial answered the question about statin effectiveness in treating the metabolic syndrome in those with a lower LDL-C (<130 mg/dL); however, these individuals also had an elevated CRP >2 mg/L (mean 4.2 mg/L). 
The AFCAPS/TexCAPS trial found that treating metabolic syndrome patients with a baseline LDL-C >150 mg/dL decreased CV events independent of CRP.43 A post hoc analysis of AFCAPS/TexCAPS suggested that there may also be benefit in treating metabolic syndrome patients with baseline LDL-C <130 mg/dL if the CRP is >1, not 2, mg/L.45 Although this later analysis was merely hypothesis-generating, it suggested there may be a subgroup of the metabolic syndrome patients with a CRP 1-2 mg/L who were excluded from JUPITER but may also benefit from statin-lowering LDL-C therapy. 
Final notes
The metabolic syndrome increases the risk of CVD independent of the baseline risk from the usual CHD risk factors.3 Although scant data exist for the individual treatment of each metabolic risk factor (elevated glucose, blood pressure, triglyceride levels, increased waist circumference, and decreased HDL-C) in reducing CV events, when the treatment strategy comprehensively addresses all abnormal metabolic risks, the result lowers the risk of CVD. In addition, aggressive lowering of LDL-C independent of treatment of metabolic risk factors lowers risk, even when LDL-C is <130 mg/dL, with the caveat that CRP is >2 mg/L and possibly even if it is only >1 mg/L. 
Further research is needed to define what combination of risk factors in the metabolic syndrome results in a greater or lesser CV risk and whether the addition of inflammatory and/or prothrombotic markers will refine the syndrome definition. 
Lastly, data are lacking on which specific therapies are most effective and, in some cases, may even be detrimental in treating any specific risk factor. The surrogate markers used for metabolic syndrome may appear to be improved without any evident clinical outcome benefit; thus, the evidence base needs to emphasize clinical outcomes rather than merely improvement in the metabolic markers for CV disease. 
 Patricia A. Hiserote DO, is the chair and an assistant professor of the Department of Primary Care, at Touro University Coll ege of Osteopathic Medicine—Cali fornia (TUCOM-CA). She can be reached at
 Michael B. Clearfield, DO, is professor and dean of Touro University College of Osteopathic Medicine—California (TUCOM-CA). Dr Clearfield is a member of the JAOA Editorial Advisory Board. He can be reached at
 This continuing medical education publication is supported by an educational grant from Merck & Co, Inc.
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Table 1
Diagnostic Criteria for Metabolic Syndrome
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Table 1
Diagnostic Criteria for Metabolic Syndrome
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