The Triad of the Metabolic Syndrome, Cardiovascular Disease, and Diabetes

The Evolution of the Metabolic Syndrome

Metabolic syndrome, which affects approximately 24% of Americans age 20 or older, is a premorbid condition that is predictive of the development of type 2 diabetes and cardiovascular disease (CVD). “Emerging evidence suggests that the prevention or control of related factors, such as abdominal obesity and inactivity, may help prevent the development of metabolic syndrome and thus also reduce the risk for type 2 diabetes and CVD,” said Anthony Hanley, PhD, Assistant Professor, Department of Medicine, University of Toronto, and Staff Scientist, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario. According to Dr. Hanley, the World Health Organization (WHO), National Cholesterol Education Program (NCEP), and American Association of Clinical Endocrinologists each recently presented criteria for the diagnosis of metabolic syndrome, allowing for more accurate study of its prevalence, risk factors, and predictive value for
diabetes and CVD.

Metabolic Syndrome Defined
Metabolic syndrome—also called syndrome X and insulin resistance syndrome—is characterized by the presence of several interrelated factors, such as abdominal adiposity, insulin resistance, and hypertension. The WHO criteria for the diagnosis of metabolic syndrome include the presence of diabetes, IGT, IFG, or hyperinsulinemia plus at least two of the following factors: overall and/or abdominal obesity, elevated triglyceride level and/or reduced high-density lipoprotein level, elevated blood pressure, and microalbuminuria (WHO, 1999). The NCEP criteria include three of the following: abdominal adiposity, elevated triglyceride level, reduced high-density lipoprotein level, elevated blood pressure, and fasting hyperglycemia (NCEP Expert Panel. JAMA 2001;285: 2486). Ford and colleagues found an overall age-adjusted prevalence of NCEP defined metabolic syndrome of 24% among Americans age 20 or older (Ford et al. JAMA 2002; 287:356). “These data show a significant percent of the US population having metabolic syndrome—and therefore increased risk for diabetes and its related complications,” Dr. Hanley noted.

Predicting Diabetes and Cardiovascular Disease
According to Dr. Hanley, insulin resistance and pancreatic beta-cell dysfunction are characteristics not only of diabetes, but also of metabolic syndrome. In the multicentered Insulin Resistance Atherosclerosis Study, results showed a significant association between metabolic syndrome and being in lowest quartile of both FSIGTT-measured insulin sensitivity and acute insulin response (a measure of beta cell function), using both WHO and NCEP definitions (Hanley et al. Diabetes 2003;52:2740). “Insulin resistance and beta-cell dysfunction are known independent predictors of type 2 diabetes. Thus, the WHO and NCEP definitions of metabolic syndrome are useful in identifying those at increased risk for diabetes and heart disease,” Dr. Hanley explained.

Indeed, several studies show metabolic syndrome to be predictive of type 2 diabetes (Lakka. Am J Epidemiol 2002;156:1070. Hanson. Diabetes 2002;51:3120. Resnick. Diabetes Care 2003;26:861). The San Antonio Heart Study, for example, followed Mexican Americans and non-White Hispanic persons for approximately 7.5 years. The results showed a significant association between NCEP-defined metabolic syndrome and the development of diabetes (Lorenzo. Diabetes Care 2003;26:3153).

Emerging evidence also suggests a possible association between metabolic syndrome and CVD. In the Kuopio Ischemic Heart Disease Risk Factor Survey (Lakka et al. JAMA 2002;288:2709), researchers found a clear increased risk of CVD-related death in men with metabolic syndrome, Dr. Hanley said. In an Italian prospective, population-based study, WHO-defined metabolic syndrome was significantly associated with the development of new coronary plaque, new stenosis, and new coronary heart disease (Bonora et al. Diabetes Care 2003;26:1251). With NCEP-defined metabolic syndrome, however, the findings have not been as consistently predictive of CVD as of type 2 diabetes (Resnick et al. Diabetes Care 2003;26:861). “Metabolic syndrome is clearly a predictor of the development of type 2 diabetes, and potentially also of CVD,” Dr. Hanley noted.

Risk Factors for Metabolic Syndrome
It is hoped that, by identifying the risk factors for metabolic syndrome, individuals may reduce their risk of developing this condition and thus also type 2 diabetes and associated comorbidities. Park and colleagues analyzed data from the Third National Health and Nutrition Examination Survey (a large representative cross-sectional survey of US adults) to identify significant independent variables associated with metabolic syndrome (Park et al. Arch Intern Med 2003;163:427). They found such risk factors to include older age, obesity, smoking, and physical inactivity in men and women; high-carbohydrate diet in men alone; and Mexican-American ethnicity, reduced socioeconomic status, and menopausal status in women alone. “Important to note is the strong association between obesity—increased body mass index—and metabolic syndrome,” Dr. Hanley said. In the prospective Kuopio Ischemic Heart Disease Study, researchers found that moderate physical activity, vigorous physical activity, and fitness level were factors independently associated with metabolic syndrome, with increased physical activity and increased fitness level protecting against the development of this condition (Laaksonen et al. Diabetes Care 2002; 25:1612). Other prospective studies have demonstrated elevated C-reactive protein concentration, elevated proinsulin, and reduced high-density lipoprotein to be predictive of metabolic syndrome (Han et al. Diabetes Care 2002;25:2016. Palaniappan et al. Diabetes Care 2004; 27:788).

In closing, Dr. Hanley stressed the importance of identification of those at increased risk for metabolic syndrome. “It appears that the prevention and treatment of obesity may be the most direct route to the prevention of metabolic syndrome and its potentially serious sequelae,” he concluded.

The Challenge of Macrovascular Disease in Diabetes and the Metabolic Syndrome

“In patients with type 2 diabetes, glycemic control alone is insufficient to prevent or limit the complications associated with diabetes-related macro-vascular disease, ” said Peter Libby, MD, Mallinckrodt Professor of Medicine, Harvard Medical School, and Chief, Cardiovascular Medicine, Brigham and Women’s Hospital, Boston. According to Dr. Libby, “Optimal management also requires aggressive treatment of hypertension and dyslipidemia, making a multi-pronged approach to management essential in persons with type 2 diabetes.”

Pathophysiology of Diabetes and Macrovascular Complications
It is well known that two thirds of people with diabetes die from cardiovascular disease (CVD), and associated macrovascular disease reaches far beyond the coronary arteries. Indeed, diabetes-related atherosclerosis involves not only coronary disease, but also stroke and critical limb ischemia (Table 1). “In understanding the pathophysiology of diabetes, it is important to note that atherosclerosis is an inflammatory disease from its inception to its ultimate thrombotic complications,” Dr. Libby said. An important driver of inflammation in this process is the adipocyte, which acts to pour out pro-inflammatory mediators, or adipokines. These adipokines are released—often from large quantities of visceral adipose tissue—into the portal circulation and liver, providing a substrate for the synthesis of low-density lipoprotein precursors and stimulating an inflammatory response. “Indeed, it appears that obesity in itself is a pro-inflammatory stimulus,” Dr. Libby explained. An analysis of the population-based Women’s Health Study showed that those with higher baseline C-reactive protein levels had an increased risk of developing diabetes (Pradhan et al. JAMA 2001;286(3):327). “Inflammation appears to be a cause in addition to a consequence of type 2 diabetes,” Dr. Libby said.

In addition, adipocytes act to increase the delivery to the liver of substrate free fatty acids for VLDL and triglyceride synthesis, and hence contribute to a preponderance of small dense low-density lipoprotein particles, an elevation in triglyceride-rich lipoproteins, and low high-density lipoprotein levels. These factors are compounded by insulin resistance in the muscle, impairing the ability to burn fat and increasing free fatty acid levels.

In diabetic and non-diabetic persons, atherosclerosis predisposes to thrombotic complications, such as stroke, acute coronary syndromes, and critical limb ischemia. In persons with metabolic syndrome or diabetes, the fibrinolytic process is impaired and the thrombotic capacity is heightened.

Targeting Hypertension and Dyslipidemia
“The most significant threat to life in persons with diabetes is macrovascular disease. While glycemic control is effective in controlling microvascular disease, other measures are needed to target macrovascular complications,” Dr. Libby said. According to Dr. Libby, the prevention of diabetes-related macrovascular disease requires a combination of lifestyle and pharmacologic intervention. First, lifestyle measures are key, as exercise and nutritional therapy can help achieve weight loss and improve insulin sensitivity.

“In addition to aggressive management of glucose levels, treatment to control hypertension and dyslipidemia is a priority,” Dr. Libby said. Research shows a clear reduction in cardiovascular endpoints with appropriate hypertension control. In those with diabetes, angiotensin-converting enzyme inhibitors and angiontensin receptor blockers may help achieve hypertension control, but also assist in preservation of renal function. In addressing dyslipidemia in patients with diabetes, statin therapy has shown a benefit in reducing cardiovascular events, including myocardial infarction and stroke. Finally, fibrate therapy may exert antiatherogenic effects, and has shown promise in preventing cardiovascular endpoints in persons with diabetes and diabetes-related dyslipidemia (Beckman. JAMA 2002;287(19): 2570).

“Emerging evidence suggests that PPAR-alpha and PPAR-gamma are potential targets in the reduction of diabetes-related macrovascular disease,” Dr. Libby said. Indeed, thiazolidinedione agents may be used to target PPAR-gamma, expressed by macrophages in atherosclerotic plaque (Marx et al. Am J Pathol 1998;153(1):17). In pilot studies, for example, the use of a PPAR-gamma agonist in humans retarded the progression of intimal thickening as measured by carotid intima-media thickness (Xiang. Diabetes 2002;5:A174. Kosh-iyama. J Clin Endocrinol Metab 2001; 86(7):3452).

In closing, Dr. Libby noted that both lifestyle and pharmacologic interventions are essential to reducing the risk of macrovascular complications in persons with metabolic syndrome or type 2 diabetes. “The optimal management of type 2 diabetes must involve not only aggressive management of hyperglycemia, but also control of the underlying pathophysiologic components of macrovascular complications—including obesity, hypertension, and dyslipidemia,” he
concluded.

Current Management of Type 2 Diabetes and the Metabolic Syndrome

Diabetes—a complex metabolic disorder characterized by elevated blood glucose concentrations and increased risk for microvascular and macrovascular complications—affects an estimated 194 million people. Along with obesity, the prevalence of diabetes is on the rise, and is expected to afflict 333 million by the year 2025 (WHO, 2003). “In patients with type 2 diabetes, aggressive lifestyle and multidrug strategies are required to manage the disease and prevent or delay associated cardiovascular complications,” said Edward S. Horton, MD, Professor of Medicine, Harvard Medical School, and Vice President and Director of Clinical Research, Joslin Diabetes Center, Boston. According to Dr. Horton, this same treatment approach may help reduce the risk of developing type 2 diabetes in persons who have metabolic syndrome.

Preventing Progression to Diabetes
There is increasing evidence that insulin resistance and pancreatic beta-cell dysfunction are among the earliest defects in the pathogenesis of type 2 diabetes, occurring before overt diabetes develops. Their interaction plays an important role in the progression from impaired glucose tolerance to diabetes, as well as progressive worsening of existing diabetes.
According to Dr. Horton, the three main goals in treating metabolic syndrome include: 1) prevention of progression from impaired glucose tolerance to type 2 diabetes; 2) prevention of cardiovascular complications; and 3) prevention of other associated comorbidities, such as obesity and insulin resistance.

Current treatment strategies focus on reducing insulin resistance and preserving beta-cell function. Both lifestyle and pharmacologic therapies have been effective in reducing the progression from metabolic syndrome to type 2 diabetes. In the DPP study of individuals at risk for diabetes, a 31% reduction in risk of diabetes was observed in persons receiving metformin and a 58% reduction in risk in those undergoing lifestyle intervention (Diabetes Prevention Program Research Group. New Eng J Med 2002;346:393). Similarly, the TRIPOD study showed a 55% reduction in development of diabetes in those receiving troglitazone compared with placebo (Buchanan et al. Diabetes 2002, 51: 2796). “This protective effect is clearly due to the insulin-sensitizing effect of thiazolidinedione therapy, providing an improvement in progression to diabetes—and potentially a direct effect on preservation of beta-cell function,” Dr. Horton explained.

Reducing the Risk of CVD
According to National Cholesterol Education Program guidelines, persons with diabetes are considered at equal risk for a cardiovascular disease (CVD) event as those with coronary heart disease. This was shown clearly in a Finnish study in which the 7-year incidence of fatal/nonfatal myocardial infarction was greater in persons with diabetes who had no history of myocardial infarction than in non-diabetics who had a previous myocardial infarction (Haffner et al. N Engl J Med 1998;339:229). Insulin resistance itself is associated not only with metabolic syndrome and type 2 diabetes, but also with an increased risk of CVD in patients with these conditions. This may be due to an independent effect on the cardiovascular system, or an indirect effect via the association of insulin resistance with dyslipidemia, hypertension, and/or vascular abnormalities such as endothelial dysfunction and low-grade inflammation.

Based on time to first CVD event, the UKPDS study showed the rank of baseline risk factors for coronary artery disease to be low-density lipoprotein, followed by high-density lipoprotein, hemoglobin A1C, and systolic blood pressure (Turner et al. BMJ 1998;316:823) (Table 1). UKPDS data also demonstrated myocardial infarction and microvascular endpoints to be associated with increasing hemoglobin A1C levels (Stratton et al. BJM 2000;321:405).

“To reduce the risk of CVD in persons with type 2 diabetes, intensive glycemic control and treatment of insulin resistance are key. In addition, a multifactorial treatment strategy to reduce individual risk factors—such as dyslipidemia and hypertension—is needed,” Dr. Horton said. In addition to key lifestyle modification measures (nutrition, exercise, smoking cessation), various pharmacologic therapies have shown a benefit in persons with type 2 diabetes. In the Heart Protection Study, for example, statin therapy resulted in a significant reduction of major vascular events and mortality in persons with diabetes or occlusive vascular disease (Pyorala et al. Diabetes Care 1997;20: 614). Similarly, in the REVERSAL trial, intensive and moderate statin therapy regimens produced a significant reduction in cholesterol and CRP levels (Nissen et al. JAMA 2004:291:1071). “Importantly, ultrasound examination showed that the lower the cholesterol levels, the greater the decrease in atheroma volume,” Dr. Horton explained. Dr. Horton added that research is currently ongoing to investigate the potential benefit of PPAR agonists in targeting low-density lipoprotein, high-density lipoprotein, and triglyceride levels, either alone or in combination with statin therapy.

Another important therapeutic target in persons with metabolic syndrome or diabetes is hypertension. Indeed, the UKPDS trial demonstrated that for every 10-mmHg reduction in systolic blood pressure, a significant reduction in microvascular disease, peripheral vascular disease, myocardial infarction, and heart failure is observed. In the HOT trial, researchers showed that reduction of diastolic blood pressure to 80 mmHg in persons with diabetes reduced the risk of CVD (Hansson et al. Lancet 1998; 351:1755). “These data show that targeting both diastolic and systolic blood pressures is critical in patients with diabetes. ACE-inhibiting antihypertensive therapy is the first-line treatment; however, a combination of two or three agents—such as angiotensin II receptor antagonists, calcium channel antagonists, and beta blockers—is often required for effective management of hypertension,” Dr. Horton said.

Finally, with effective glycemic control, the UKPDS data showed a major protective effect against microvascular disease, but a lesser impact on CVD risk. According to Dr. Horton, emerging evidence suggests that thiazolidinedione agents provide an insulin-sensitizing effect, but are also under study for their potential to reduce inflammation and CVD risk. In addition, new therapies, such as incretin agents, GLP-1 analogs, and DPP-IV inhibitors, may prove to be beneficial additions to the armamentarium of oral agents for the treatment of persons with type 2 diabetes.

In closing, Dr. Horton emphasized the need for a “multifactorial and aggressive treatment approach for persons who have or are at increased risk for type 2 diabetes, targeting not only effective glycemic control, but also obesity, dylipidemia, hypertension, and underlying processes such as endothelial dysfunction and low-grade inflammation.”