Hyperglycemia, type 2 diabetes and CVD risk

• Many patients with type 2 diabetes are at high risk of CVD. This increased risk is often similar to that of non-diabetic patients who have experienced myocardial infarction.
• A wealth of evidence indicates that hyperglycemia is a significant contributor—but not the sole contributor—to the increased CVD risk that comes with diabetes.
• Intensive blood glucose control reduces microvascular complications but does not have a substantial effect on macrovascular disease in patients with type 2 diabetes.
• The metabolic syndrome is very common in diabetic patients, and those with diabetes and the metabolic syndrome have the highest CHD rates.
• Evidence is mounting that it is not the hyperglycemic state per se that has the biggest impact on CVD in type 2 diabetes but rather the clustering of abdominal obesity-related risk factors. These factors may be responsible for the high incidence of cardiovascular events in diabetes.

Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) [1]. In fact, heart disease is the leading cause of death among patients with type 2 diabetes [2]. In a seminal study, Haffner et al. [3] noted that the risk of cardiovascular complications in diabetic patients was similar to that of non-diabetic patients who had experienced myocardial infarction. The link between diabetes and CVD is complex and not fully understood.

People with diabetes have a higher CVD risk, possibly because they also tend to have traditional risk factors such as obesity, hypertension, and dyslipidemia [4]. Other authors have suggested, however, that factors related to diabetes itself—such as hyperglycemia and hyperinsulinemia—could explain this elevated CVD risk [1].

The insulin resistance and hyperinsulinemia that occur long before the onset of diabetes are commonly accompanied by other cardiovascular risk factors, including abdominal obesity, dyslipidemia, and hypertension as well as proinflammatory and prothrombotic factors [5]. This cluster of risk factors is known as the metabolic syndrome, which commonly precedes the development of type 2 diabetes and is associated with an increased risk of type 2 diabetes and CVD [6].

After the onset of insulin resistance, fasting and postprandial glucose levels may remain in the “normal” range for several years. During this period, pancreatic β-cells are able to increase insulin secretion in response to insulin resistance and thereby maintain normal plasma glucose. When glucose metabolism worsens among prediabetic individuals, postprandial glucose levels increase and lead to impaired glucose tolerance (IGT), defined as elevated 2-h glucose levels after a glucose load (75 g). IGT usually accompanies long-standing insulin resistance. A patient with IGT is at high risk for both CVD and type 2 diabetes [7]. Only some insulin-resistant or glucose-intolerant individuals will develop type 2 diabetes. Most insulin-resistant-hyperinsulinemic subjects will not develop type 2 diabetes [8]. Several population studies have established a relationship between fasting glucose levels and CVD risk in non-diabetic subjects [9]. Moreover, a number of studies have shown that hyperinsulinemia—a marker of early insulin resistance—increases CVD risk, even in the absence of diabetes [10]. Whether or not hyperinsulinemia itself predicts macrovascular complications in patients with type 2 diabetes remains hotly debated [11]. It has also been suggested that insulin resistance is a crucial factor underpinning increased CVD risk. Hyperinsulinemia is probably a compensatory physiological response to insulin resistance, the latter being a key contributor to type 2 diabetes development [10].

There is a wealth of epidemiological evidence indicating that hyperglycemia is an independent risk factor for cardiovascular events in diabetes [12]. Compared to diabetic subjects with lower HbA1c (glycated hemoglobin), the risk of CVD death and all CVD events in type 2 diabetic subjects increases significantly with HbA1c levels over 7.0% [13]. Further intervention studies are needed to definitively prove the cause-effect relationship between hyperglycemia and CVD. In this regard, data from the wide-ranging UK Prospective Diabetes Study (UKPDS) clinical trial [14] confirmed the findings of the previous large-scale randomized type 2 diabetes trial, the University Group Diabetes Program (UGDP) [15]. The UGDP found that intensive blood glucose control effectively reduced microvascular complications such as retinopathy and nephropathy but did not have a marked effect on macrovascular disease in patients with type 2 diabetes. Recent data suggests that postchallenge plasma glucose levels could predict CVD more accurately than fasting glucose or HbA1c levels [16]. Insulin resistance is a cause of postprandial hyperglycemia [17] and could be responsible for this relationship.