Diabetes is a major risk factor for coronary heart disease (CHD) with a >20% risk for experiencing a major coronary event within a 10-year period. According to the ATP III (Adult Treatment Panel) guidelines, diabetes is considered a coronary heart disease risk equivalent that would automatically warrant a target LDL goal <100 mg/dL.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a large multi-center research trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) to study effective treatment strategies for reducing rates of major cardiovascular events, such as a myocardial infarctions, strokes, and cardiovascular-related deaths. The three-pronged treatment approaches under investigation include management of blood glucose levels, blood pressures, and blood lipid levels.
The arm of the study comparing intensive and targeted reductions in blood glucose levels was published in the New England Journal of Medicine in June 2008. The study was prematurely stopped due to increased mortality among patients in the intensive-treatment group.
The published study enrolled 10,251 patients with type 2 diabetes, whose median glycosylated hemoglobin level (HgbA1C) was 8.1%. The participants were subsequently randomized to either receive intensive therapy (target HgbA1C <6.0%) or standard therapy (target HgbA1C 7.0 – 7.9%). There were 5128 patients in the intensive group and 5123 patients in the standard group. A subset of 4733 patients were also randomly assigned to receive either intensive antihypertensive (systolic blood pressure <120 mmHg) or standard antihypertensive (systolic blood pressure <140 mmHg) management. There were also 5518 patients randomized to receive a fenofibrate or placebo, in addition to simvastatin for control of lower-density lipoprotein (LDL) levels.
The primary outcomes evaluated were nonfatal myocardial infarctions, stroke, or deaths from cardiovascular causes (i.e., myocardial infarction, heart failure, arrhythmia, invasive cardiovascular interventions, ischemic cardiovascular disease, and vascular diseases).
About 4 months after randomization, the HgbA1C levels for the intensive- and standard-therapy groups had fallen from the median 8.1% to 6.7% and 7.5%, respectively. These had changed to 6.4% and 7.5%, respectively, at 1 year into the study. During the follow-up period, there was a statistically significantly increase in hypoglycemic episodes, fluid retention, and weight gain in the intensive-treatment group compared to the standard-treatment group. However, there was only one hypoglycemia-related death in each group.
There was no difference in the primary outcome between both groups. As for secondary outcomes, the incidence of nonfatal myocardial infarction was lower in the intensive-therapy group at 186 (3.6%) cases, while the standard-therapy group had 235 (4.6%) cases (hazard ratio 0.76; p = 0.004). However, the number of composite deaths for any cause in the intensive-therapy group was significantly higher at 257 (5.0%) deaths, compared to the 203 (4.0%) deaths in the standard-therapy group (hazard ratio 1.22; p = 0.04). Deaths attributed to cardiovascular causes were 135 (2.6%) and 94 (1.8%) cases, respectively (hazard ratio 1.35; p = 0.02). Due to the higher mortality in the intensive-therapy group, the study was discontinued after a mean of 3.5 years.
The study does not demonstrate significant reduction in major cardiovascular events with intensive glucose management (target HgbA1C <6.0%). It does however reveal the hidden danger of increased mortality. The reason for this observation is currently unclear, but it does not appear to be directly related to acute episodes of hypoglycemia. The researchers suggest some possible contributing factors: the low HgbA1C, the magnitude and rate of reduction, incidence of hypoglycemic episodes, drug-drug interactions at high doses, etc. Identifying the etiology will be important for better understanding the pathophysiology of diabetes in cardiovascular disease, while guiding future management strategies for primary and secondary cardiovascular risk prevention.
- Source
- Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
