CVD risk and type 2 diabetes: Beyond hyperglycemia

• Type 2 diabetes is a significant CVD risk factor. However, the independent contribution of hyperglycemia per se to CVD risk remains uncertain.
• The hyperglycemic state of diabetes is only one of the dysmetabolic components observed in patients, who are often abdominally obese.
• The cluster of atherogenic metabolic abnormalities now often referred to as the metabolic syndrome is known to increase the risk of type 2 diabetes and CVD.
• Intervention trials have shown that reducing body weight in overweight and obese subjects at high risk of developing diabetes could substantially reduce their risk of developing diabetes.
• Age is also an important factor to consider when evaluating the CVD risk of diabetic patients.

Type 2 diabetes is recognized as a significant cardiovascular disease (CVD) risk factor, but the independent contribution of type 2 diabetic hyperglycemia to CVD risk is rather weak. It has been proposed that this hyperglycemic state is only the tip of a huge dysmetabolic iceberg, mostly resulting from a combination of factors found in overweight and obese patients with excess abdominal fat and insulin resistance [1].

Abdominal obesity is associated with a cluster of atherogenic metabolic abnormalities that are now often referred to as the metabolic syndrome. These abnormalities include atherogenic dyslipidemia, insulin resistance, and a pro-thrombotic and pro-inflammatory state. The simultaneous presence of all these risk factors is known to increase the risk of type 2 diabetes and CVD [2]. At specific fault is excess visceral adipose tissue, which is more closely associated with a detrimental metabolic profile than excess subcutaneous adipose tissue [3]. This observation has led to the widespread use of waist circumference (a surrogate measure of visceral adipose tissue) in epidemiological analyses and as a metabolic syndrome identification criterion [4,5]. In the Insulin Resistance in Atherosclerosis Study (IRAS), high waist circumference predicted the incidence of metabolic syndrome more accurately than directly measured insulin resistance [6]. Moreover, a prospective study has been published on the predictive power of high initial levels of visceral fat as a type 2 diabetes risk factor [7]. Intervention trials have also confirmed the strong association between excess body fat and type 2 diabetes found in observational studies. These trials have shown that reducing body weight in overweight and obese subjects at high risk of developing diabetes could substantially reduce the incidence of diabetes [8-10].

Besides glucose, various plasma lipid variables also play a role in increasing CVD risk. The regulation of lipoprotein and vascular physiology appears to be related to normal insulin sensitivity. Insulin resistance is associated with the typical dyslipidemic profile seen in patients with type 2 diabetes. This profile is characterized by increased levels of fasting triglycerides, low levels of HDL cholesterol, and elevated concentrations of small, dense LDL, which is the most atherogenic component of LDL cholesterol [16]. Results from a recent study revealed that in coronary patients with type 2 diabetes, the low HDL cholesterol/high triglyceride pattern correlates with the prevalence of coronary artery disease and significantly predicts the incidence of vascular events, but the LDL-related factor does not [17]. It is generally accepted based on data from numerous studies that high triglyceride-low HDL cholesterol dyslipidemia is an independent risk factor for CVD among people with diabetes [18]. Accordingly, three intervention trials have shown improvement in CVD risk with successful treatment of diabetes-related dyslipidemia [19].

A major population-based retrospective cohort study [22] of 379,003 diabetic patients and 9,018,082 non-diabetic individuals showed that for both men and women, diabetes conferred a degree of risk equal to ageing roughly 15 years. Age also appeared to be an important predictor of CVD in people with diabetes, with CVD risk rising in the late 40s for both men and women. Moreover, diabetes greatly attenuated the usual protective effect enjoyed by women, narrowing the relative gender gap in cardiovascular risk [23]. Age should therefore be taken into account when aiming to reduce CVD risk in people with diabetes.

It behoves those involved in treating diabetes or its complications to recognize that weight loss is the best way to prevent type 2 diabetes in overweight and obese subjects with impaired glucose tolerance. Many clinicians remain very much focused on improving glycemic control and blood lipids rather than inducing weight loss, and few diabetic clinics provide treatment or support that truly focuses on weight management. More holistic approaches to treating diabetes are needed, including one that does not only rely on expensive drugs to treat each dysmetabolic component. Effective weight management interventions should be initiated as soon as diabetes—or even pre-diabetic states such as impaired glucose tolerance or abdominal obesity—are diagnosed. The term “diabesity” has been coined because it reflects both etiology and clinical presentation. Its use could help ensure that excess body fat (abdominal obesity in particular) takes its rightful place as the major cause of type 2 diabetes [24].