Cadiovascular Risk Factors in Metabolic Syndrome - Impact of Insulin Resistance on Lipids, Hypertension, and the Development of Diabetes and Cardiac Events

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The clustering of cardiovascular (CV) risk factors associated with insulin is known as 'syndrome XÔÇÖ, the 'deadly quartetÔÇÖ, and 'dysmetabolic syndromeÔÇÖ among others. In addition to the clustering of obesity, hypertension (HTN), glucose intolerance, high triglycerides, and low high-density lipoprotein (HDL), other metabolic abnormalities have been associated with this syndrome, including impaired fibrinolysis and a proinflammatory diathesis. This syndrome is most commonly recognized today as metabolic syndrome (MS) and affects approximately 24% of the US adult population. According to the Third National Health and Nutrition Examination Survey (NHANES III), MS affects nearly 50 million people, including 44% of subjects over the age of 50.

MS is closely associated with obesity, which has shown a disturbing increase in prevalence, both in the US and worldwide, creating an unprecedented risk for CV disease (CVD). Obesity is prevalent across all demographic groups and is non-gender-specific. Nearly two-thirds of all adult Americans are now considered overweight or obese. Obesity is also rampant in children and adolescents, with 50% of severely obese youngsters meeting MS criteria. Pathologic studies have shown that obesity is associated with accelerated atherosclerosis in the young, with traditional risk factors accounting for only 15% of the effect of obesity on atherosclerosis. It is now estimated that the lifetime risk of developing diabetes for children born in 2000 is 33% to 39%.

MS increases the risk of CVD, even in the absence of overt diabetes mellitus (DM), with a two- to four-fold increased risk of myocardial infarction (MI) and stroke in both men and woman. The strongest association with CV events is seen with hypertriglyceridemia and low HDL cholesterol, although HTN and glucose abnormalities are also independent predictors of the prevalence of CVD. Insulin-resistant subjects have lower HDL levels and higher systolic blood pressure and triglyceride levels compared with normal subjects well before they develop diabetes, leading to the 'ticking-clockÔÇÖ hypothesis. In the Nurse Health Study, women who developed DM during follow-up had a 3.8-fold increase in risk of MI prior to their diagnosis of DM, as well as a 4.6 relative CV risk for the period after the diagnosis of DM. Diabetes is now considered a cardiovascular risk equivalent (meaning that by the time diabetes is diagnosed the patient has likely already established CVD. MS is an even more striking predictor of DM than CV events. Men with multiple features of MS have over a three-fold increased risk of CV events and a 20-fold increased risk of DM.

The central components of CV risk in MS are visceral (central) obesity and resultant insulin resistance. Although obesity is a powerful risk factor for DM and CVD, substantial heterogeneity exists in the distribution of fat and the relationship between metabolic disturbances and obesity. A significant minority of obese subjects are not insulin-resistant and, conversely, lean subjects may be insulin-resistant. Adipocytes secrete multiple pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-╬▒), and it is now well appreciated that MS is a proinflammatory condition, leading to increased vascular oxidative stress and the early development of endothelial dysfunction. Adipocytes also secrete and influence the actions of multiple signaling molecules ('adipokinesÔÇÖ), such as leptin, resistin, and adiponectin that contribute to insulin resistance and CV risk. For example, adiponectin levels are inversely correlated with insulin resistance and coronary artery disease (CAD).

It has been estimated that 30% of IL-6 production comes from adipocytes and directly influences the hepatic production of C-reactive protein (CRP). CRP levels vary in direct proportion to the number of metabolic abnormalities. Chronic subclinical inflammation is an important part of MS, as CRP is independently related to obesity, insulin sensitivity, and MS itself. CRP remains a highly significant predictor of both DM and CV events when adjusted for other CV risk factors. In addition to correlating well with all five of the easily measured components of MS, CRP also correlates with insulin resistance, endothelial dysfunction, and impaired fibrinolysis. Environmental factors (high caloric density diet and sedentary lifestyle) are also dominant factors in the epidemic of obesity and MS and the search continues to define specific genetic abnormalities associated with MS.

The lipoprotein abnormalities of MS (increased levels of triglycerides and triglyceride rich particles, small dense low-density lipoprotein (LDL) particles, with marked reductions in HDL (including HDL-2 particles)) are extremely atherogenic and play an enormous role in the development of CV events. Hypertriglyceridemia leads to low HDL levels and increased sd-LDL particles, primarily due to the activity of cholesterol ester transfer protein (CETP).Triglyceride-rich HDL is hydrolyzed by hepatic lipase, and, to a lesser extent, lipoprotein lipase, which generates smaller HDL particles. Small dense HDL particles shed apolipoprotein-A1, which is then catabolized in the kidney. Similarly, VLDL triglyceride is exchanged for LDL cholesterol in the presence of CETP. The hydrolysis of LDL triglyceride generates sd-LDL particles.

To capture the risk of triglyceride remnants, the calculation of non-HDL cholesterol is helpful when triglycerides exceed 200mg/dl. Small dense LDL is associated with a three-fold increased CV risk compared with larger LDL particles. Optimization of glycemic control by insulin and thiazolidinediones (TZDs) improves LDL particle size, as does treatment with niacin. Statins markedly reduce total LDL concentrations, but generally do not alter particle size distribution. Fibrate therapy typically increases particle size, but clinical data is conflicting. Patients with established CVD and multiple risk factors of MS (especially elevated triglycerides, non-HDL cholesterol, and low HDL-C) are considered very high risk; this favors treatment to a lower LDL goal of <70mg/dl.

MS nearly doubles the CV risk associated with HTN, above and beyond the effects of traditional risk factors in both men and women. MS is also associated with over a two-fold increase risk of chronic renal disease and a 34% increase in microalbuminuria compared with controls. Microalbuminuria in itself is associated with a doubling of CV risk and mortality, independent of traditional CV risk factors.

HTN is associated with an incidence rate of approximately 2% per year of the development of new onset DM, which appears to be independently associated with CV events. Patients with new onset DM on hypertensive therapy had a CV event rate that was nearly three-fold higher than subjects who remained without diabetes throughout treatment. Treatment with angiotensin receptor antagonists/blockers (ARBs), angiotensin receptor inhibitors (ACE-Is), and calcium channel blockers (CCBs) is associated with a lower incidence of DM compared with beta blockers (BBs) and diuretics. Although BBs uniformly worsen insulin sensitivity, the addition of alpha blockade appears to improve insulin sensitivity. In the COMET trial, carvedilol was associated with a 22% lower incidence of new onset DM compared with metoprolol in heart failure patients. Although there are no official guidelines for the treatment of hypertensive subjects with MS, recent data would suggest the use of ACE-Is or ARBs for MS patients with impaired glucose metabolism or micro-albuminuria. There may also be rational for ARB/ACE-I combinations in hypertensive patients with glucose intolerance.

Given the markedly increased risk of developing DM and CV events, early recognition of metabolic abnormalities and efforts at primary prevention are of paramount importance. Lifestyle modifications remain the cornerstone of therapy and should be combined with aggressive pharmacologic control of metabolic factors when warranted. A multifactorial intervention involving lifestyle modifications and aggressive pharmacologic therapy in high-risk diabetic patients with microalbuminuria was associated with a 50% lower risk of CVD compared with conventional treatment of modifiable risk factors. An aggressive approach appears to be similarly warranted in high-risk MS subjects.

Weight loss, dietary modification, and exercise are the cornerstones of lifestyle interventions in MS. Weight loss through diet and exercise, but not liposuction, reduces inflammatory markers in obese patients. Modest weight loss and regular exercise reduces the risk of developing DM by 50%, which is better than the results achieved with medication, in high-risk patients with glucose abnormalities. Alpha glucosidase inhibitors, TZDs, and orlistat also appear to retard the development of DM in high-risk subjects, which may result in improved CV outcomes. Bariatric surgery can also markedly improve glucose metabolism in obese subjects and may be appropriate in selected subjects.

Conclusions

MS is associated with an increased risk of CV above and beyond the contribution of its individual metabolic components. Visceral adiposity and associated insulin resistance are associated with a pro-inflammatory and pro-thrombotic state, as well as the release of adipokines, which may both directly and indirectly influence atherogenesis. Hypertension and hyperlipidemia in the presence of MS greatly enhances CV risk. MS is also associated with a marked increase risk in the development of DM, especially in the presence of impaired glucose metabolism.The development of DM while on treatment for hypertension appears to portend an increased risk of CV events comparable with subjects with hypertension and established DM. Identification of metabolic risk factors and aggressive lifestyle interventions are warranted in all patients, with aggressive pharmacologic intervention when appropriate.