Minimizing the Risks for Cardiovascular Disease
Steven M. Haffner, MD
Dr. Haffner acknowledged the recent debate about the metabolic syndrome: whether it exists, what causes the clustering of metabolic disorders not likely to occur by chance alone, and the pathogenesis of the syndrome.
Insulin resistance is widely considered the foundation of the metabolic syndrome. Visceral fat is more often associated with insulin resistance than lower body obesity and subcutaneous fat. It is associated with higher plasma levels of fatty acids, which allow accumulation of triglycerides in muscle, cause hepatic fat accumulation, and produce pro-inflammatory adipokines, thus resulting in increased insulin resistance. Insulin resistance is also associated with atherogenic dyslipidemia, hypertension, glucose intolerance, impaired fibrinolysis, inflammation, polycystic ovary syndrome, and nonalcoholic fatty liver disease.
The elevated risk of cardiovascular disease starts well before the development of type 2 diabetes. The Nurses Health Study revealed nearly a 3-fold increased risk of cardiovascular disease in subjects who later developed type 2 diabetes. For many years, the American Diabetes Association recommended early screening followed by intensive glycemic control. However, if cardiovascular disease risk is increased before the development of diabetes, this early screening may miss people who are at high risk. Identifying metabolic syndrome may help to improve prediction. The American Diabetes Association has pointed out a number of problems with the concept of the metabolic syndrome and the varying cutpoints used in different definitions. Cutpoints established for risk in the United States cannot be used around the world. The individual components of metabolic risk differ in the predictive ability for diabetes and cardiovascular disease. It is not clear that the metabolic syndrome predicts cardiovascular disease independently of its components. Further, it is not clear that there is a single etiology for the syndrome.
The metabolic syndrome may be a useful operational definition for cardiometabolic risk and it may encourage healthcare providers to examine other risk factors. These risk factors are usually addressed independently rather than treating the root cause, which remains controversial.
Current therapy directed at the metabolic syndrome includes, first, lifestyle changes, particularly weight loss and exercise. Treatment of individual components-hyperlipidemia, hypertension, obesity, and so on-is the norm. Dr. Haffner does not believe that metabolic syndrome, like diabetes, is a CHD “risk equivalent.” Use of individual insulin-sensitizing agents is most likely not appropriate in patients with metabolic syndrome as there are no clinical studies to support this approach, but this is not the case with type 2 diabetes. However, he suggests performing an oral glucose tolerance test to determine the presence of 1) diabetes, which should be treated with insulin sensitizers; or 2) impaired glucose tolerance, which may be treated because data from the Diabetes Prevention Project, STOP-NIDDM, and TRIPOD suggest value in this case. If the patient has normal glucose tolerance with the metabolic syndrome, treatment with insulin sensitizers is not appropriate. Controlling Hyperglycemia in Insulin-resistant Patients
Barry J. Goldstein, MD, PhD
Dr. Goldstein noted that the American Diabetes Association meetings have presented exciting new modalities of treatment for insulin resistance and how they might be integrated into clinical practice. The treatment goal is normal glucose control. However, the definitions of normal vary. According to the American Diabetes Association, these are as follows: HbA1c as close to normal as possible, preprandial plasma glucose <110 mg/dL, and 2-hour postprandial glucose <140 mg/dL. These are not as robust as the European criteria, and Dr. Goldstein has questioned the varying criteria.
More stringent glycemic goals (HbA1c <6%) may further reduce complications, but at the expense of an increased risk of hypoglycemia. Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals.
The tight connection between diabetes and cardiovascular disease is linked to impaired endothelial function. There is increased understanding that any level of glucose rise contributes to oxidative stress and the endothelial dysfunction that results from it; HbA1c is not the only factor. Glucose excursions have a significant effect on measures of oxidative stress in patients with diabetes. When the glucose level rises and drops frequently, the body cannot achieve an antioxidant strategy. The damage from frequent glucose elevations can lead to reactive oxidative species. The EPIC-Norfolk study for example, showed that HbA1c predicted cardiovascular mortality in men not known to have type 2 diabetes, and the DECODE study found that fasting plasma glucose and postprandial glucose levels predicted mortality in persons not known to have type 2 diabetes.
In the metabolic syndrome, abdominal adiposity is associated with a number of atherogenic changes and correlates negatively with insulin sensitivity. Insulin resistance is a core defect in type 2 diabetes, characterized by overproduction of glucose by the liver and impaired glucose uptake by skeletal muscle. In analyses from the San Antonio Heart Study, Dr. Haffner and his coworkers found that converters to diabetes had both insulin resistance and low insulin secretion in a majority of cases, and that insulin resistant prediabetic subjects had more atherogenic risk factors than insulin-sensitive prediabetic subjects, suggesting that strategies to prevent diabetes based on insulin-sensitizing interventions would lower cardiovascular risk.
Results from the EPIC-Norfolk study showed that HbA1c predicted cardiovascular mortality in men not known to have type 2 diabetes, and the DECODE study demonstrated that fasting plasma glucose and postprandial glucose levels predicted mortality in persons not known to have type 2 diabetes.
To get the HbA1c close to normal, patients must understand not only what HbA1c is, and what is normal, but what this means in terms of glucose levels, which should be close to normal, or the HbA1c will not be close to normal. Treatments that lower glucose aggressively without causing hypoglycemia-thiazolidinediones, metformin, and, potentially, a GLP-1 agonist-are appropriate.
What causes hyperglycemia? The liver overproduces glucose in the absence of adequate insulin, indicating insulin resistance in the liver; a fatty liver is a part of this problem. More recently, however, the role of glucagon is being examined. Glucagon is secreted at high levels in patients with diabetes. GLP-1 agonists lower glucagon, which then helps to lower liver glucose production and allows whatever insulin is available to work more efficiently, possibly with agents such as metformin, and to a lesser extent, thiazolidinediones.
A paradigm of treatment is that one does not need much of an increase in fasting glucose to develop glucose toxicity; it may start with a fasting glucose of 115-120 mg/dL. This is a good rationale for aggressive treatment at the beginning of the disease course. This may help to prevent the loss of β-cell function. However, the majority of patients with type 2 diabetes have inadequate glucose control-nearly two thirds of persons in the United States and worldwide have HbA1c levels >7. This has led to the “Control to Goal Initiative”: if the patient’s HbA1c is not ≤7 within 6 months of starting treatment, a more aggressive treatment strategy should be initiated.
Treatment options begin with lifestyle changes: reducing fat and total calorie intake, losing weight, increasing exercise, stopping smoking, and good glucose control have been shown to have remarkable effects. When good glucose control cannot be achieved by lifestyle options, pharmacologic options are important. Metformin helps to reduce glucose production in the liver. Thiazolidinediones have their initial effect in adipose tissue and stimulate intake of glucose in muscle and, to a lesser extent, in the liver. Thiazolidinediones dramatically increase adiponectin while reducing secretion of free fatty acids and tumor necrosis factor-α and reducing inflammatory infiltrate into visceral fat, thereby increasing glucose metabolism in muscle and liver. They stimulate insulin secretion in the β-cell, which is adversely affected by free fatty acids and cytokines. Thiazolidinediones have beneficial vascular effects in the endothelium. Thus, they have a role completely different from metformin. Rosiglitazone has been shown to dramatically improve β-cell function.
If combination therapy is required, metformin and a thiazolidinedione are often beneficial. If these don’t work together, the patient may not have enough insulin to support these drugs. Insulin secretagogues-sulfonylureas-improve insulin secretion. However, they can frequently cause hypoglycemia, particularly early in the course of diabetes. They may also exacerbate visceral fat accumulation and cause ischemic preconditioning. The newer sulfonylureas, such as glyburide and glimepiride, are less toxic for the heart and the vasculature. Sulfonylureas should be used with caution in patients with hepatic or renal dysfunction. If sulfonylureas are inadequate, insulin may need to be added to the regimen.
Exenatide, one of the newest drugs, is not being used yet as first-line therapy. It is in a class of drugs known as incretin mimetics or GLP-1 agonists. The effects on glucose control seen with exenatide treatment are believed to be due to several properties that are similar to those of the naturally occurring incretin hormone GLP-1. These actions include stimulating the insulin response in response to glucose and preventing glucagon release after meals. However, it must be injected, which many patients find problematic.
Amylin analogs decrease the release of glucagon, slow the rate of gastric emptying, and increase satiety, which, in conjunction with insulin, leads to a reduction in blood glucose values. Blood glucose reductions are greater with the combination of amylin and insulin compared to insulin alone. In patients with insulin insufficiency, there is reduced amylin secretion. Pramlintide is the first amylin analog to be approved by the FDA for use in patients with type 2 diabetes who have failed to obtain desired glucose control with insulin therapy, with or without a sulfonylurea or metformin. It is also approved in patients with type 1 diabetes who have not achieved desired glucose control despite optimized insulin therapy. Pramlintide is administered by subcutaneous injection.
Other agents on the horizon are cannabinoid receptor blockers, which appear to regulate energy balance and body composition. Blocking the action of these receptors is an attractive target for treating obesity, diabetes, and the metabolic syndrome. Peroxisome proliferator activated receptor-α-γ agonists have been recently tested but studies have been discontinued due to serious safety concerns. Modulating the Lipid Profile in Patients with Dyslipidemia
Kelly Anne Spratt, DO
The elevated risk of cardiovascular disease starts before the clinical diagnosis of diabetes; before a patient is diagnosed with diabetes, the risk is almost 3-fold higher than in those who do not develop diabetes.
High plasma cholesterol levels are a strong predictor of cardiovascular events in patients with diabetes. The cardiovascular mortality rate is 2.83 to 4.46 times higher in diabetic men than in nondiabetic men at various levels of serum cholesterol. In the UK Prospective Diabetes Study, high levels of low-density lipoprotein cholesterol (LDL-C) most highly correlated with cardiovascular events. However, low levels of high-density lipoprotein cholesterol (HDL-C) were almost equally significant as predictors of cardiovascular events.
LDL-C levels do not account for the heterogeneity in LDL and other lipoprotein subclasses that characterizes insulin resistance. As a result, the cardiovascular risk in diabetic patients with metabolic syndrome is underestimated when these levels are used as predictors. Lipoprotein subclass abnormalities that accompany insulin resistance are characterized by large, triglyceride-enriched very low-density lipoprotein (VLDL) particles; small, cholesterol-depleted LDL particles; and small HDL particles. In addition, more severe states of insulin resistance have been associated with progressively higher numbers of VLDL particles, intermediate-density lipoprotein particles and, most important, LDL particles.
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