Effect of glycemic control on cardiovascular disease

Improved blood glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unclear. This is particularly true when older medications are used to treat hyperglycemia. Previously, there was concern that sulfonylureas may increase cardiovascular mortality in patients who have type 2 diabetes mellitus and that high insulin concentrations may enhance atheroma formation. In the UKPDS trial, however, the effects of intensive blood glucose control, with either sulfo-nylurea or insulin and conventional treatment, on the risk of microvascular and macrovascular complications in patients who had type 2 diabetes mellitus were compared in a randomized, controlled trial [8].

A previous study that was performed in the 1970s, the University Group Diabetes Program (UGDP), concluded that tolbutamide treatment may increase cardiovascular mortality. Criticism of the methodology that was used in the study and the poor overall glycemic control that was achieved reduced the impact of the study. The large (1000 mg) dosage of tolbutamide that was taken in the morning by subjects who were assigned this treatment resulted in a high plasma level for several hours that was followed by a rapid decline due to hepatic clearance.

The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial is particularly relevant to the impact of glycemic control for cardiology practice. A total of 620 patients were studied; 306 were randomized to treatment with insulin-glucose infusion that was followed by multi-dose subcutaneous insulin for at least 3 months and 314 were randomized to conventional therapy. After 1 year, 57 subjects (18.6%) in the infusion group and 82 subjects (26.1%) in the control group had died (relative mortality reduction 29%, P = 0.027). The mortality reduction was particularly evident in patients who had a low cardiovascular risk profile and no previous insulin treatment (3-month mortality rate was 6.5% in the infusion group and 13.5% in the control group [relative reduction 52%, P = 0.046]; 1-year mortality rate was 8.6% in the infusion group and 18.0% in the control group [relative reduction 52%, P = 0.020]). Insulin-glucose infusion that was followed by a multi-dose insulin regimen improved long-term prognosis in diabetic patients who had acute myocardial infarction [12]. Whether the insulin effect was due to withdrawal of sulfonylurea in DIGAMI is not clear.

Insulin resistance and cardiovascular disease

Many of the features of insulin resistance that are present before the onset of hyperglycemia remain operative during the natural history of the diabetes mellitus and contribute greatly to atherosclerosis and associated comorbidities [13,14]. Insulin resistance contributes to the development of atherosclerosis through multiple recognizable risk factors, such as hypertension, dyslipidemia, and hypercoagulability (see Fig. 1) [15].

Insulin resistance and compensatory hyper-insulinemia contribute to hyperglycemia in type 2 diabetes mellitus and may play a pathophysiologic role in a variety of other metabolic abnormalities, including high levels of plasma triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, hypertension, abnormal fibrinolysis, and coronary heart disease [15,16]. This cluster of abnormalities has been called the insulin resistance syndrome or the metabolic syndrome [17]. The National Cholesterol Education Program Adult Treatment Panel III recently recognized the metabolic syndrome as a secondary therapeutic target for the prevention of cardiovascular diseases [15]. Patients who have the metabolic syndrome meet at least three of the following criteria: triglycerides that are greater than 150 mg/dL, HDL that is less than 40 mg/dL, blood pressure that is greater than 130/85 mm Hg, fasting blood glucose that is greater than 110 mg/dL, and waist circumference that is greater than 40 cm in men or 50 cm in women (Table 1) [15].

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