|Year : 2009 | Volume
| Issue : 1 | Page : 17-26
Reducing cardiovascular risk in the metabolic syndrome: What we know and what we still need to know
Antonio M Gotto
, Jr, M.D., DPhil, Stephen and Suzanne Weiss Dean and Professor of Medicine, Weill Cornell Medical College, New York, USA
|Date of Web Publication||17-Jun-2010|
Antonio M Gotto
Jr, MD, DPhil, c/o Jennifer Moon, PhD., Weill Cornell Medical College, 1305 York Ave. Y-806, New York, NY 10021
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Since its identification as a group of cardiovascular risk factors that frequently cluster together, the metabolic syndrome has been the subject of controversy. Several definitions exist, and some commentators claim that the diagnosis of the metabolic syndrome may not even be clinically useful. Nevertheless, it is clear that the factors that comprise the syndrome-elevated levels of triglycerides, low levels of high-density lipoprotein cholesterol, elevated blood pressure, elevated blood glucose, and abdominal obesity-even considered individually, increase the risk for cardiovascular disease and need to be treated, and that risk increases with the number of risk factors present. This review will discuss the predictive value and approaches to treatment of each of the risk factors comprising the metabolic syndrome and will provide a justification for that designation. In addition, it will pose several questions that remain to be answered in order for us to provide optimal prevention strategies and treatment for this increasingly prevalent syndrome adults.
Keywords: Metabolic syndrome, cardiovascular disease
|How to cite this article:|
Gotto AM. Reducing cardiovascular risk in the metabolic syndrome: What we know and what we still need to know. Heart Views 2009;10:17-26
| Definitions|| |
The metabolic syndrome is characterized by a constellation of metabolic risk factors that in concert increase cardiovascular morbidity and mortality. Within the Gulf nations, metabolic syndrome rates are high. Using the definition of the metabolic syndrome of the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III), the Persian Gulf Healthy Heart Study found that the prevalence of metabolic syndrome in a population drawn from three Iranian ports was 52.1%  . In the United Arab Emirates, the age-adjusted prevalence of metabolic syndrome was approximately 40% in 2000  . In Qatar, rates of hypertension, obesity, and impaired glucose tolerance are high and greatly increase the risk for developing metabolic syndrome, cardiovascular disease, and diabetes , .
Definitions of the metabolic syndrome vary across organizations. According to ATP III guidelines, a diagnosis of the metabolic syndrome requires the presence of any three of the following: abdominal obesity as determined by waist circumference, triglycerides ≥150 mg/dL, high-density lipoprotein cholesterol (HDL-C) < 40 mg/dL in men or < 50 mg/dL in women, blood pressure ≥130/85 mm Hg, and fasting blood glucose ≥110 mg/dL  . ATP III recognizes the metabolic syndrome as a potential secondary target of cardiovascular risk-reduction therapy after the primary target of low-density lipoprotein cholesterol (LDL-C).
Insulin resistance is not one of the NCEP's defining criteria, and it is unknown whether insulin resistance plays a causative role in the development of metabolic syndrome. The Framingham Offspring study found that 56% of persons with the ATP III definition of the metabolic syndrome were also insulin resistant  . Insulin resistance is included in the World Health Organization's definition of the metabolic syndrome, a fact that some investigators believe may lessen its predictive value for cardiovascular disease in some populations  . Recently, obesity, rather than insulin resistance, has been seen as possibly the key feature of the metabolic syndrome.
The International Diabetes Federation has proposed a diagnosis of the metabolic syndrome based on the presence of central obesity and any 2 of the following: triglycerides > 150 mg/dL or specific treatment for hypertriglyceridemia; HDL C < 40 mg/dL in men or < 50 mg/dL in women, or specific treatment for low HDL C; blood pressure ≥130/85 mm Hg or treatment for previously diagnosed hypertension; and fasting blood glucose ≥100 mg/dL or a previous diagnosis of type 2 diabetes mellitus  . Sex-specific and ethnicity-specific cut-off points are provided for central obesity.
The American Diabetes Association and the European Association for the Study of Diabetes have issued a joint statement questioning the value of the metabolic syndrome as a diagnosis. They argue that it remains imprecisely defined and that it may be premature to consider it a "syndrome"  . The American Diabetes Association statement points out that the individual components of the syndrome have long been known to convey increased cardiovascular risk and argues that the risk associated with the metabolic syndrome as a whole may not be greater than the sum of its parts. Although cardiovascular risk increases incrementally with the number of risk factors, it is currently debated whether the metabolic syndrome represents a greater pathology than the sum of its individual component ,, .
| What We Know About the Predictive Value of the Metabolic Syndrome|| |
Numerous studies have confirmed that the metabolic syndrome is a significant predictor of cardiovascular disease and type 2 diabetes  . For example, over an 11-year follow-up in the Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based prospective cohort study of 1,209 initially healthy, middle-aged Finnish men, participants with the metabolic syndrome (NCEP definition) were 2.9 to 4.2 times (depending on waist circumference) more likely to die from coronary heart disease (CHD) compared with persons without the syndrome  . In a prospective study of 6,255 subjects with the metabolic syndrome in the United States, persons with even 1 or 2 characteristics of the NCEP-defined metabolic syndrome were at increased risk for mortality from CHD and cardiovascular disease  . In addition, the metabolic syndrome has been shown to be independently associated with nonfatal ischemic heart disease, as assessed by electrocardiogram, in the Persian Gulf Healthy Heart Study  .
Post hoc analysis of two large statin trials, the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), lend further support to the hypothesis that the metabolic syndrome (NCEP definition) carries an increased risk not fully accounted for by traditional scoring methods in both primary and secondary prevention  . Placebo-treated patients from 4S were 1.5 times and from AFCAPS/ TexCAPS 1.4 times more likely to have a major coronary event than patients without metabolic syndrome.
| Metabolic Syndrome Characteristics as Predictors of Cardiovascular Risk|| |
HDL-C. A low HDL-C (< 35-40 mg/dL for men and < 35-50 mg/dL for women) is one of the strongest predictors of CHD risk, although clinical trial data have not yet demonstrated conclusively that increasing HDL-C levels reduces CHD risk. The Framingham Heart Study found that each 1-mg/dL increment in HDL C was associated with an approximate 2% reduction in CHD risk  . Post hoc analysis of the recent Treating to New Targets (TNT) study found that HDL-C remains predictive of time to a first major cardiovascular event even in patients who have achieved very low levels of LDL-C (< 70 mg/dL) while on statin therapy  .
The association between high triglyceride levels and abnormally low levels of HDL-C in the metabolic syndrome makes it difficult to establish whether elevated triglycerides independently predict cardiovascular morbidity and mortality  . However, in a meta-analysis of 21 population-based studies comprising 76,952 persons, each mmol/L (89 mg/dL) increase in triglyceride levels was associated with a 12% increase in CHD risk in men and a 37% increase in women, after adjustment for total cholesterol, LDL-C, HDL-C, body-mass index, blood pressure, and diabetes  . Moreover, elevated triglycerides appear to be associated with elevated fibrinogen levels, more platelet aggregation, and less fibrinolytic activity-all factors that contribute to cardiovascular risk -than lower triglyceride levels  . Some evidence suggests that elevated triglycerides may predict cardiovascular risk more reliably in women than in men  .
The relationship between blood pressure and the risk of cardiovascular events is continuous, consistent, and independent of other risk factors, although the presence of additional risk factors compounds the risk from hypertension  . After 40 years of age, mortality from both ischemic heart disease and stroke doubles for every increase of 20 mm Hg systolic or 10 mm Hg diastolic  . In a hypertensive Saudi population, presence of metabolic syndrome, as defined by ATP III and WHO, more than doubled the risk for coronary heart disease  . Cardiovascular damage may occur more frequently in hypertensive persons with metabolic syndrome than in those without it due to increased inflammation and fibrosis associated with the metabolic syndrome  .
Insulin resistance and impaired plasma glucose:
In a large Danish population-based study, insulin resistance was shown to predict cardiovascular disease independently of the metabolic syndrome. This study also suggested that insulin resistance may be the cause of 50% of cases of the metabolic syndrome and may be a factor in the pathogenesis of cardiovascular disease  .
Persons with diabetes are at a 2 to 4-fold increased risk of cardiovascular events compared with those without diabetes, but even persons with "prediabetes" (impaired fasting glucose or impaired glucose tolerance) are considered to be at increased risk for cardiovascular disease as well as for diabetes , . In a population of Qatari nationals, 16.7% were diabetic, and 13.8% were found to be pre-diabetic  .
Improved glucose control is known to reduce the risk of diabetic microvascular disease, and it is currently debated whether it may also reduce the risk of cardiovascular events  . Results from the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicate that intensive therapy to reduce glycated hemoglobin levels to normal in patients with type 2 diabetes did not reduce the risk of major cardiovascular events and instead increased mortality rates  . After 3.5 years of treatment, findings of increased mortality in the intensive-therapy group led to discontinuation of the intensive therapy arm of the study. Standard therapy to manage glucose levels remains the recommended course of treatment.
Abdominal obesity is a risk factor for hypertension, hyperinsulinemia, elevated levels of inflammatory markers, increased fibrinogen levels, and premature atherosclerosis  . For this reason, waist circumference may provide a more accurate prediction of cardiovascular risk than body mass index  . In the INTERHEART Study, both waist-to-hip ratio and waist and hip circumferences, but not body mass index, were closely associated with the risk of myocardial infarction, even after adjustment for other risk factors  . In a study of Omani Arab women, waist circumference was found to be the strongest predictor of metabolic syndrome, compared to body mass index and other IDF criteria for metabolic syndrome  . In a separate study of obesity among Omani Arabs, the authors suggest that lower cut-off points for waist circumference and body mass index for men and higher cut-off points for women might be more accurate among Arab populations than existing guidelines, which are drawn from studies of European populations  .
Recent investigations suggest that dysfunction in adipose tissue accounts for increased cardiovascular risk. In obese individuals, adipose tissue contains macrophages that release proinflammatory cytokines into the circulation  . While the mechanisms by which inflammation may affect clinical outcomes are not yet fully understood, ongoing research utilizing measures of high-sensitivity C-reactive protein (hs-CRP), an inflammatory biomarker, suggests that systemic inflammation is pro-atherogenic and may help predict cardiovascular risk  .
| What We Know About Treatment|| |
Based on data from the U.S. National Health and Nutrition Examination Survey (NHANES) III, it is estimated that optimal control of 3 risk factors-blood pressure, LDL-C, and HDL-C-could prevent > 50% of CHD events in men with the metabolic syndrome and approximately 43% of events in women  . Clinicians should consider both lifestyle and pharmacologic interventions to reduce the severity of these cardiovascular risk factors and the other risk factors of the metabolic syndrome.
Lifestyle modification is appropriate for all patients with risk factors above specified cut points. Approaches to management of the metabolic syndrome for persons at low short-term risk should begin with lifestyle interventions aimed at weight loss and increased physical activity, combined with treatment of the individual component risk factors  . Patients should be encouraged to reduce their calorie consumption by 500 to 1000 per day, in order to reduce their body weight by about 7% to 10% over a 6 to 12-month period  .
Aggressive lifestyle modification has been shown to reduce the prevalence of the metabolic syndrome and also to prevent its onset in patients with impaired fasting glucose , . Risk factors can mediate the association between overweight and CHD, and weight reduction may decrease the risk of CHD through its mediating effect on those risk factors  . Weight control alone, in addition to lowering LDL-C, has further benefits on all the components of the metabolic syndrome. Despite aggressive lifestyle modification, however, patients with the metabolic syndrome who are at high or moderately high 10-year risk may require pharmacologic therapy.
Triglycerides and HDL-C. The NCEP and American Heart Association guidelines for treatment of the metabolic syndrome defined diagnostic cut points for high triglycerides and low HDL-C but did not make them specific targets for therapy. While lifestyle measures can lower triglycerides in persons with borderline high levels (150-199 mg/dL), those with high or very high levels may need therapy with statins, fibrates, niacin (nicotinic acid), or omega-3 fatty acids (fish oils); these agents have been reported to lower triglycerides by up to 50%. Statin therapy has been shown to produce the greatest benefit in patients with elevated LDL-C who also had the highest baseline triglyceride levels and the lowest HDL-C levels, as compared to patients who simply had elevated levels of LDL-C  .
Fibrates (PPAR- agonists) may be particularly effective in reducing cardiovascular risk in patients with high triglyceride and low HDL-C levels. In a post hoc analysis of the Bezafibrate Infarction Prevention study in patients with CHD, participants with the highest baseline triglyceride levels (≥ 200 mg/dL) experienced a highly significant 39.5% reduction in risk with fibrate therapy vs. placebo  . In the Veterans Affairs HDL-C Intervention Trial, a secondary prevention trial of gemfibrozil in men with HDL-C < 40 mg/dL, gemfibrozil reduced the risk of CHD death and nonfatal myocardial infarction by 22% relative to placebo during a median follow-up of 5.1 years  . Gemfibrozil decreased the risk of these CHD events by 11% for each 5-mg/dL increase in HDL-C; these results were independent of baseline and on-treatment LDL-C levels, as well as triglycerides  . Comparable results were reported in primary prevention with gemfibrozil in the Helsinki Heart Study  . Results from the recent Fenofibrate Intervention and Event Lowering in Diabetes study were mixed in diabetic patients treated with fenofibrate  . This study failed to reach its primary endpoint of reduction in coronary events, although it did show a significant decrease in total cardiovascular events, largely due to a decrease in revascularization procedures and non-fatal myocardial infarction.
Another class of drugs, the thiazolidinediones (PPAR- agonists) are insulin sensitizers indicated for treatment of type 2 diabetes, although one member of the class, troglitazone, was withdrawn because of findings of hepatic toxicity and another, rosiglitazone, has recently been under intense scrutiny due to a meta-analysis reporting an increased risk of myocardial infarction with its use  . However, pioglitazone has not been associated with an increase in adverse effects. The Prospective Pioglitazone Clinical Trial in Macrovascular Events enrolled 5238 patients with type 2 diabetes and a history of macrovascular disease who were randomized to pioglitazone or placebo, in addition to their regular glucose-lowering and other medications  . There was a non-significant trend towards benefit in the primary composite endpoint of all-cause mortality or major cardiovascular event, and patients treated with pioglitazone had significantly greater reductions in LDL-C and triglycerides and a greater increase in HDL-C than patients on placebo.
In terms of therapies that specifically target HDL-C, the Multiple Risk Factor Intervention Trial found that CHD mortality in men declined by 16% for each 5-mg/dL increase in HDL-C among nonsmokers, and by 7% among smokers  . Smoking cessation will effectively increase HDL-C levels in current smokers, and other pharmacological options are available. Nicotinic acid has the greatest effect on increasing HDL-C levels (15%-35%), with fibrates (6%-15%) and statins (3%-15%) having a more moderate effect  . The ongoing AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low LDL/High Triglycerides and Impact on Global Health Outcomes) study is designed to assess nicotinic acid's HDL-raising capacity in combination with statin therapy in patients with the metabolic syndrome. Another approach to raising HDL-C has focused on inhibiting cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to very-low-density lipoproteins (VLDL) and LDL, as well as the transfer of triglycerides from VLDL to LDL and HDL. Torcetrapib, the first CETP inhibitor to be evaluated in large clinical trials, produced dose-related increases in HDL-C when administered alone or in combination with atorvastatin to patients with low HDL-C levels , . However, the development of torcetrapib was halted after an interim analysis of an outcome study showed excess mortality, which may have been molecule-specific rather than due to CETP inhibition in general , . The ongoing development of other CETP inhibitors will need to be watched closely due to safety concerns.
Other approaches for improving HDL levels or function currently under investigation include a recombinant form of apolipoprotein A1 Milano, a naturally occurring variant of apolipoprotein A1 found in people with very low HDL C but with little evidence of atherosclerosis, and apolipoprotein A1-mimetic peptides, a still experimental approach for improving HDL function , .
Blood pressure. A wealth of evidence shows that lowering blood pressure is associated with a clinically important reduction in the risk of cardiovascular morbidity and mortality  . Achieving targets < 140/90 mm Hg is associated with a decrease in cardiovascular complications  . Patients with hypertension plus diabetes or renal disease should achieve blood pressure goals < 130/80 mm Hg  . It is estimated that a 5-mm Hg reduction of systolic blood pressure across the general population would result in overall reductions of 14% in stroke mortality, 9% in CHD mortality, and 7% in all-cause mortality  .
Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are the best agents for treatment of hypertension in patients with the metabolic syndrome. Thiazide diuretics have been associated with the development of diabetes in these patients, while-blockers have been associated with increases in triglyceride levels, increases in insulin resistance, and worsening glucose control  .
Abdominal obesity. Weight loss in obese individuals decreases cardiovascular risk  , but no clinical trial has investigated directly the effects of reduction in abdominal obesity on the risk of CHD. Therefore, the exact extent to which cardiovascular risk is reduced by decreasing abdominal obesity is currently unknown.
A growing body of evidence suggests that bariatric surgery may lead to remission in diabetes, with a return to normal glucose and insulin levels achieved without medications within days of surgery  . Since changes occur so quickly, it is unlikely that weight loss or reductions in abdominal obesity alone are responsible for these dramatic improvements. It is hypothesized that gastrointestinal bypass operations effect a beneficial rearrangement in gastrointestinal anatomy, perhaps involving bypass of the small bowel in particular, although exact mechanisms remain under investigation.
Impaired glucose tolerance. For persons with impaired glucose tolerance, treatment with insulin-sensitizing agents may be considered. However, insulin-sensitizing agents have not been shown to reduce risk of CHD in persons who do not have diabetes. Agents such as cannabinoid receptor antagonists and peroxisome proliferator-activated receptor antagonists may also be useful.
The role of statins in the metabolic syndrome. About 60% of persons with the metabolic syndrome have, in addition to elevated triglyceride and low HDL-C levels, elevated levels of LDL-C. LDL particles in these individuals are often small, dense, and numerous, which increases the atherogenic state. Because of their beneficial effects on the lipid profile, in addition to their anti-inflammatory effects, statins play an important role in the treatment of the metabolic syndrome ,, .
In the Scandinavian Simvastatin Survival Study, major coronary event rates were highest in participants with elevated LDL-C and triglyceride levels and the lowest HDL-C levels  . In persons with impaired fasting glucose, treatment with simvastatin reduced major coronary events by 38%, total mortality by 43%, and coronary mortality by 55%  .
The Comparative study with rosuvastatin in subjects with METabolic Syndrome (COMETS) was the first prospective, randomized trial of statin therapy in patients with the metabolic syndrome  . In COMETS, 401 patients with the metabolic syndrome and a 10-year CHD risk score of > 10% were randomized to receive either rosuvastatin 10 mg, atorvastatin 10 mg, or placebo for 6 weeks, after which statin doses were doubled for another 6 weeks and the placebo group received rosuvastatin 20 mg. At 6 and 12 weeks, significant LDL-C reductions were seen in rosuvastatin-treated patients vs those receiving atorvastatin. More patients receiving rosuvastatin increased their HDL-C level and achieved their LDL-C goals. Both statins were well tolerated in this group of multiple-risk-factor patients. Similar results were seen in a post hoc analysis of 811 patients with NCEP-defined metabolic syndrome in the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, in which rosuvastatin was compared with atorvastatin, simvastatin, and pravastatin. All statins had favorable effects on atherogenic dyslipidemia, with rosuvastatin generally having the greatest effect Table  . [Additional file 1]
Subgroup analyses of major clinical trials suggest that (a) statins may produce greater benefit in patients with the metabolic syndrome than in those without it , and (b) aggressive statin therapy may decrease cardiovascular risk more than moderate statin therapy in patients with the metabolic syndrome  . The Justification for the Use of Statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which was recently stopped after a median follow-up of 1.9 years due to early evidence of benefit, enrolled a large number of patients with the metabolic syndrome (41%) within the overall study population of healthy men and women with low LDL-C and elevated hs-CRP levels  . Treatment with rosuvastatin vs. placebo resulted in a 47% relative reduction in the combined end point of myocardial infarction, stroke, or cardiovascular mortality and a 20% relative reduction in total mortality. Benefit was similar in patients both with and without metabolic syndrome.
| What We Still Need to Know|| |
Many questions surrounding the metabolic syndrome, from definitions to optimal treatment, continue to generate controversy. Future research can help clarify:
- the relationship of metabolic syndrome to conventional risk factors in the calculation of global risk;
- the role of insulin resistance and glucose control in the metabolic syndrome;
- the effect of lifestyle measures alone in the reduction of cardiovascular risk in patients with the metabolic syndrome;
- optimal targets for therapy in persons with the metabolic syndrome;
- the role of hs-CRP and other markers of inflammation in the metabolic syndrome.
| Conclusion|| |
Cardiovascular disease is a multifactorial condition with multiple etiologies. Risk factors for cardiovascular disease commonly cluster in persons with either a genetic predisposition to them or specific behaviors that enhance risk. The term "metabolic syndrome" is a clinically useful designation for many reasons. First, even well-controlled LDL-C may leave residual risk. An emphasis on triglycerides and HDL-C-both of which are currently undertreated-reminds us that controlling risk needs to go beyond LDL C lowering  . Second, because not all the NCEP risk factors for metabolic syndrome are included in the Framingham Risk Score, persons with the metabolic syndrome may not be considered at sufficiently high risk on the basis of that formula alone  . Third, while individual risk factors must reach clinical levels before treatment is recommended, a diagnosis of metabolic syndrome increases the calculated global risk and therefore might indicate treatment even when individual abnormalities are not dramatic. Statins that can effectively lower LDL-C and triglycerides as well as raise HDL-C may be a useful option to treat the multiple risk factors seen in metabolic syndrome. Future clinical trials and treatment guidelines will need to address the issue of multiple-risk-factor intervention, particularly in patients with the metabolic syndrome .
Acknowledgements: AstraZeneca provided a grant to support the research and editorial work for the preparation of this paper. The author had complete control over the writing and editorial content. He would like to thank Ruth Sussman, PhD at Landmark Programs and Jennifer Moon, PhD at Weill Cornell Medical College for their research and editorial assistance.
Disclosure: Dr. Gotto is a current consultant for Genentech, KOWA, Martek, and Merck, and he serves on the board of directors for Aegerion and Arisaph Pharmaceuticals. He also serves on advisory boards for DuPont and Novartis. He has consulted for AstraZeneca in the past.
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