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Preventing Adverse Cardiovascular Events in Patients with Type 2 Diabetes

In younger patients with newly diagnosed diabetes, intensive glucose-lowering therapy appears to prevent macrovascular events; in patients with established diabetes, the jury is still out.

Intensive glucose-lowering therapy is widely believed to prevent macrovascular complications in patients with type 2 diabetes. However, results from several recent trials have cast doubt on this assumption.

In the ACCORD trial, researchers randomized about 10,000 type 2 diabetic patients (mean age, 62) with known cardiovascular (CV) disease or at least two CV risk factors to either intensive glucose-lowering therapy or standard therapy. Glycemic control was significantly better in the intensive-treatment group (glycosylated hemoglobin [HbA_1c]_, 6.4% vs. 7.5%). However, after a mean follow-up of 3.5 years, the intensive-treatment group had significantly higher mortality than the standard-treatment group did (5% vs. 4%; P=0.04). Furthermore, no differences were noted between the groups in CV death, myocardial infarction, or stroke (JW Jun 6 2008).

In the ADVANCE trial, investigators randomized more than 11,000 type 2 diabetic patients (mean age, 66) with known microvascular or macrovascular disease or one risk factor for CV disease to either intensive glucose-lowering therapy or standard therapy. After a median follow-up of 5 years, the intensive-treatment group had significantly better glycemic control (HbA_1c, 6.5% vs. 7.3%) and experienced fewer microvascular events (the main event in both groups was nephropathy). However, no differences were found between the groups in mortality or major adverse CV events (JW Jun 6 2008).

Researchers from the United Kingdom Prospective Diabetes Study (UKPDS) randomized about 4000 patients (median age, 54) with new-onset type 2 diabetes to either intensive glucose-lowering therapy or standard therapy. After a median follow-up of 11 years, the intensive-treatment group had significantly better glycemic control (HbA_1c, 7.0% vs. 7.9%) and experienced fewer microvascular events (mainly, requisite retinal photocoagulation). No differences were found between the groups in macrovascular events or mortality at the close of the randomized portion of the study (JW Oct 2 1998). More than 3000 UKPDS patients were followed after trial completion, and their HbA_1c levels became similar within 1 year. After 10 years, however, the patients who were initially in the intensive-therapy group experienced significantly fewer microvascular events, fewer MIs, and lower mortality (JW Oct 14 2008).

The UKPDS involved younger patients with new-onset type 2 diabetes, whereas patients in ACCORD and ADVANCE had established diabetes and end-organ complications or CV risk factors. These observations suggest that intensive glucose-lowering therapy holds more promise for younger, newly diagnosed, type 2 diabetic patients; however, this hypothesis should be confirmed by additional trials. For older diabetic patients with end-organ complications or CV risk factors, perhaps the best approach is to achieve "reasonable" glycemic control (HbA_1c, about 7.0%); avoid hypoglycemic events; and focus on diet, exercise, smoking cessation, weight loss, blood pressure control, and lipid lowering. Indeed, in a recent trial, investigators found that such a multifactorial approach lessened microvascular and macrovascular events and excess deaths in type 2 diabetic patients during 13 years of follow-up (JW Feb 6 2008).

As we were going to press, another randomized controlled trial of intensive glucose control was published (JW Dec 24 2008). In a study from U.S. Veterans Affairs hospitals, almost 1800 patients with type 2 diabetes who were at high risk for vascular events were randomized to conventional or tight glycemic control. At a median of 5.6 years of follow-up, tight control was not associated with longer time to reach the primary endpoint (a composite of MI, stroke, cardiovascular death, heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene).

— Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine December 29, 2008