Clinical Feature: Gender Differences in the Diagnosis and Treatment of the Metabolic Syndrome

The metabolic syndrome is a clustering of interrelated risk factors for cardiovascular (CV) disease and type 2 diabetes. Although various definitions for the metabolic syndrome exist, several national and international health organizations — including the American Heart Association (AHA); the National Heart, Lung and Blood Institute (NHLBI); and the International Diabetes Federation (IBF) — have proposed a harmonized definition for the metabolic syndrome.¹ By this definition, the metabolic syndrome is diagnosed when three of the following five risk factors are present: (1) abdominal obesity that is gender-, population- and country-specific, (2) elevated blood sugar, (3) high blood pressure, (4) low levels of high-density lipoprotein (HDL) cholesterol, and (5) elevated triglycerides. In addition to waist circumference, the level of HDL cholesterol used to define the metabolic syndrome differs between men and women. Low HDL cholesterol is defined as < 40 mg/dL for men and < 50 mg/dL for women. (Table 1)

Underlying these metabolic risk factors is adipose tissue dysfunction and insulin resistance. In the metabolic syndrome, increased free fatty acids delivered to the liver also increases hepatic secretion and triglyceride enrichment of very-low- density lipoprotein (VLDL) cholesterol. Incomplete lipolysis of VLDL particles leads to an accumulation of triglyceride-rich remnant lipoproteins, and triglyceride enrichment of HDL cholesterol via cholesteryl  ester transfer protein (CETP) results in smaller HDL particles and low levels of HDL cholesterol.² Although low- density lipoprotein (LDL) cholesterol is not specifically part of the metabolic syndrome, people with the metabolic syndrome have a high concentration of small, dense LDL cholesterol particles. The atherogenic dyslipidemia associated with the metabolic syndrome is an important risk factor for CV disease. The presence of the metabolic syndrome is associated with a two-fold increased risk of CV disease and a five-fold increased risk of type 2 diabetes.³ In this article we examine gender differences in the metabolic syndrome, focusing on the associated atherogenic dyslipidemia.

Gender Differences in the Prevalence of Metabolic Syndrome

The most current estimates from the National Health and Nutrition Examination Survey (NHANES) are that 23.7 percent of men and 21.8 percent of women in the U.S. have the metabolic syndrome.⁴ This translates into more than 37 million men and more than 36 million women in the U.S. who have the metabolic syndrome. In another analysis from NHANES, the prevalence of the metabolic syndrome was shown to increase with age for both sexes but was greater in older women compared to older men.⁵ (Figure 1) About 20 percent of men and 16 percent of women under the age of 40, and 41 percent of men and 37 percent of women between the ages of 40 to 59 met the criteria for the metabolic syndrome. In people over the age of 60, 54 percent of women met the criteria for the metabolic syndrome compared to 52 percent of men. There also are differences between men and women in the individual risk factors that constitute the metabolic syndrome. Men have a higher age-adjusted prevalence of hypertriglyceridemia, hypertension, and hyperglycemia than women, while women have a higher age-adjusted prevalence of abdominal obesity and low HDL cholesterol compared to men. For women, the prevalence of abdominal obesity, hypertriglyceridemia, hypertension, and hyperglycemia increases with age. In contrast, in men, only the prevalence of hypertension and hyperglycemia increases with age.⁵ Among younger women, the most prevalent metabolic syndrome combination is the clustering of high triglycerides, low HDL cholesterol, and increased waist circumference. In older women, the presence of all five risk factors is the most prevalent metabolic syndrome combination.⁶ Although the overall age-adjusted prevalence of the metabolic syndrome has fallen for both men and women in the past decade, it has increased in younger and middle-aged women.^4,7 The increasing prevalence of the metabolic syndrome in younger women is primarily the result of an increase in abdominal obesity in this group. The rates of the metabolic syndrome are highest among non-Hispanic black and Mexican American women (Figure 2) and women in the lowest economic strata.⁸

The difference between men and women in the prevalence of the metabolic syndrome and its individual components may be explained in part by differences in central fat distribution, hormonal factors, and the onset of menopause. Both increasing waist circumference and age are associated with an increase in visceral adipose tissue (VAT) and VAT is more strongly correlated with metabolic syndrome and cardiovascular risk than is subcutaneous adipose tissue.9 Younger women have a lower prevalence of the metabolic syndrome compared to younger men, and this may be because younger women have less VAT than men, even after correcting for total body fat. Compared to younger men, younger women need to accumulate significantly more total body fat before increases in visceral fat are observed, however, the increasing trend of obesity in younger women may well erase any gender benefit that younger women enjoy. For men, age-related increases in VAT are greater than for women, however, after menopause, VAT accumulation in women increases rapidly, to a rate similar to that of men.¹⁰ Furthermore, estrogen decline in menopause stimulates adipocyte hypertrophy and leads to adipocyte dysfunction, which may lead to more visceral fat accumulation.¹¹ It is the increase in abdominal obesity and the postmenopausal state that leads to the increased prevalence of metabolic syndrome in older women.

Gender Differences in the Risk of CV Disease and Diabetes

Metabolic syndrome is associated with an up to two-fold increase in CV disease, CV mortality, stroke, and all-cause mortality.¹² For both men and women, the presence of three or more components of metabolic syndrome is a stronger predictor of CV and all-cause mortality than when fewer components are present.¹³ Compared to CV risk, the metabolic syndrome has been shown to be an even stronger predictor for diabetes. Across many populations, including Europeans, Asians, Hispanics, and those of Middle Eastern descent, the presence of the metabolic syndrome is associated with a five-fold increase in the risk of diabetes.¹⁴

Several meta-analyses have shown that the CV risk conferred by the metabolic syndrome is higher in women than in men.^12,15,16 In one meta-analysis that included 172,573 people, the CV risk associated with the metabolic syndrome was a third higher in women than in men.¹⁶ There are several possible reasons for the higher CV risk in women with the metabolic syndrome.¹² After menopause, central adiposity is more pronounced in women than in men and the lipid profile is different in post-menopausal women compared to men. After menopause, HDL cholesterol decreases, LDL cholesterol increases, and LDL particle size shifts to smaller and denser particles. Among people with the metabolic syndrome, HDL cholesterol has been shown to be a stronger predictor of CV events in women compared to men.¹⁷ Furthermore, there is evidence that triglycerides are more highly associated with CV disease in women than in men.¹⁸ Other studies have shown no gender differences in CV risk in metabolic syndrome.^17,19 In a prospective population-based study of 1,260 older people in Finland who were followed for nine years, fatal and non-fatal coronary, cerebrovascular, and all vascular events occurred more commonly in people with the metabolic syndrome compared to those without the metabolic syndrome. However, in this study, the vascular risk was lower in women than in men.¹⁷ The different findings among studies that gender confers on CV risk may be related to differences in the definition used to diagnose the metabolic syndrome, heterogeneity in patient populations, and the inclusion of studies with a small sample size in some of the meta-analyses. Although these studies may differ in whether the metabolic syndrome confers a higher CV risk in women than in men, the consistent finding among these studies is that the metabolic syndrome in women is a strong predictor of increased CV risk.

Gender Differences in the Treatment of the Metabolic Syndrome

The primary goal of treating the metabolic syndrome is to reduce the risk of CV disease. The first-line treatment of the metabolic syndrome is lifestyle modification directed at weight loss and increased physical activity. A reduced- calorie diet of between 1,200 and 1,500 kcal/d for women and between 1,500 and 1,800 kcal/d for men is recommended to achieve a weight loss of approximately 5 to 10 percent of initial body weight.²⁰ Both men and women lose weight on a low-calorie diet, however, studies suggest that men, on average, lose more weight than women, despite diets with similar caloric restrictions. In a study of 133 younger men and women with risk factors for the metabolic syndrome, men had a significantly lower waist circumference than did women after following a Mediterranean-style diet for 12 weeks.²¹ In addition, changes in triglyceride levels and in the ratio of total cholesterol to HDL cholesterol were significantly more pronounced in men than in women. In an observational study of a weight- management program sponsored by the National Health Service in the United Kingdom, men, on average, lost almost 4 pounds more than women over a 12-week period, almost 7 pounds more than women in six months, and more than 11 pounds more than women by the end of one year.²² These findings are consistent with previous research that indicates men lose more weight than women when engaged in weight-loss intervention. There are several possible explanations for these findings. Men may have a higher starting weight than women, women may already have better baseline dietary habits than men, or other psychosocial factors may be at play. However, irrespective of these gender differences, lifestyle modifications alone often are insufficient to address the CV risk factors associated with metabolic syndrome, leaving both men and women at increased CV risk.

When lifestyle changes alone are unsuccessful, pharmacologic therapy to target the dyslipidemia associated with the metabolic syndrome is recommended. Statins are the drug of choice and are effective in lowering not only LDL cholesterol, but also triglyceride-rich remnant lipoproteins; they also have favorable effects on the size and concentration of LDL cholesterol particles.²³ Post-hoc analyses from several clinical outcome studies have shown that statin therapy reduces major CV events in patients with the metabolic syndrome.^24,25 Studies show that women derive the same CV-event-reduction benefit from statins as men.²⁶ Despite the benefits women derive from statin therapy, high-risk women tend to be less aggressively treated with statin therapy compared to high-risk men.²⁷

Although the new ACC/AHA cholesterol-lowering guidelines28 do not specifically address the metabolic syndrome nor set cholesterol goals for treatment, most people who have the metabolic syndrome will have a high CV risk score or other indications that would warrant statin therapy. The National Lipid Association (NLA)²⁹ and several international societies^30,31 also recommend lipid-lowering therapy for people with the metabolic syndrome and, in contrast, to the ACC/ AHA cholesterol guidelines, have set both LDL and non-HDL cholesterol goals for these patients. In patients with the metabolic syndrome, non-HDL cholesterol may be a better predictor of CV risk than LDL cholesterol. Among people with a discordantly high non-HDL compared to LDL cholesterol, CV risk may be underestimated when only LDL cholesterol is considered.³² To this point, the recent NLA cholesterol guidelines have placed non-HDL ahead of LDL cholesterol as a therapeutic target.²⁹

Many patients with the metabolic syndrome will be considered high-risk and their LDL and non-HDL cholesterol goals may be difficult to achieve with statin therapy alone. Subgroup analyses from other clinical trials suggest that fibrates, niacin, and omega-3 fatty acids may further reduce CV risk in statin-treated patients with high triglycerides and low HDL cholesterol^33,35 and the recent IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed the added benefit of additional LDL cholesterol lowering when ezetimibe was added to statin therapy.³⁶ Several studies have found that high-risk women are less likely to achieve  optimal  LDL and non-HDL cholesterol goals compared to men. In a study of 9,950 coronary artery disease patients in the U.S., of whom 34 percent were women, women were less likely to achieve an LDL cholesterol goal of < 70 mg/dL and a non-HDL cholesterol goal of < 100 mg/dL compared to men. In the Dyslipidemia International Survey-China (DYSIS-China), women with the metabolic syndrome were less likely to achieve their non-HDL cholesterol goals compared to men.³⁷ In both of these studies, combination lipid-lowering therapy was infrequently used.

Conclusions

The metabolic syndrome is common, occurring in more than one-half of postmenopausal women. Because of the increase in obesity, the prevalence of the metabolic syndrome is on the rise, especially in younger women. Women with the metabolic syndrome are at increased CV risk, and the metabolic syndrome may confer a higher CV risk in women than in men. To reduce the CV risk associated with the metabolic syndrome, lifestyle interventions need to target the dyslipidemia and other risk factors of the metabolic syndrome. When lifestyle changes alone fail to achieve a patient’s target lipid goals, pharmacologic therapy often is needed. Statins should be the foundation of lipid-lowering therapy, however, many people with the metabolic syndrome will likely benefit from combination lipid-lowering therapy to target both LDL and non-HDL cholesterol. Clinicians need to be aware of the gender differences that exist in the prevalence and treatment of the metabolic syndrome. However, irrespective of gender, early recognition and treatment of the metabolic syndrome is essential to prevent CV events.   

Disclosure statement: Dr. Karalis received consulting fees from Aegerion. Dr. Auberson has no disclosures to report. Dr. Naqvi has no disclosures to report.

References are listed on page 38 of the PDF.