Objectives

The purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness.

Background

Glycemia Trial:
Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.

The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients.

Lipid Therapy Trial:
Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease.

Blood Pressure Trial:
Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of < 140 mm Hg.

EYE Substudy:
Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients.

MIND Substudy:
Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain.

Subjects

10,251 patients with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. They were aged 40–79 years with history of cardiovascular disease or 55–79 years with anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two risk factors for cardiovascular disease. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. Patients were eligible to participate in the lipid trial if they had the following: an LDL cholesterol level of 60 to 180 mg per deciliter (1.55 to 4.65 mmol per liter), an HDL cholesterol level below 55 mg per deciliter (1.42 mmol per liter) for women and blacks or below 50 mg per deciliter (1.29 mmol per liter) for all other groups, and a triglyceride level below 750 mg per deciliter (8.5 mmol per liter) if they were not receiving lipid therapy or below 400 mg per deciliter (4.5 mmol per liter) if they were receiving lipid therapy. Patients with a systolic blood pressure between 130 and 180 mm Hg who were taking three or fewer antihypertensive medications and who had the equivalent of a 24-hour protein excretion rate of less than 1.0 g were also eligible for the blood-pressure trial.

EYE Substudy:
A subgroup of 2856 patients was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Patients who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded.

MIND Substudy:
A subgroup of 2977 patients was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded patients aged <55 years and those in the Veteran’s Administration CCN (to retain the overall sex balance reflected in the other CCNs). Within ACCORD MIND a group of 632 patients participated in the MRI sub-study.

Design

Patients were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level <6.0%) or standard therapy (targeting a glycated hemoglobin level of 7.0 to 7.9%). Of these patients, 5518 with dyslipidemia were also randomly assigned, in a 2-by-2 factorial design, to receive simvastatin (to reduce low-density lipoprotein [LDL] cholesterol levels) in combination with either fenofibrate (to reduce triglyceride levels and increase high-density lipoprotein [HDL] cholesterol levels) or matching placebo. The remaining 4733 patients were randomly assigned, in a 2-by-2 factorial design, to undergo either intensive blood-pressure control (targeting a systolic blood pressure <120 mm Hg) or standard therapy (targeting a systolic blood pressure <140 mm Hg). The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke or death from cardiovascular causes. Clinic staff and patients were not blinded to treatment arm. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies.

EYE Substudy:
EYE Substudy patients were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.

MIND Substudy:
The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses.

Conclusions

Glycemia Trial:
As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (NEJM. 2008; 358(24): 2545-59).

Microvascular Outcomes of the Glycemia Trial:
Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Lancet. 2010; 376(9739): 419-30)

Lipid Therapy Trial:
The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (NEJM. 2010; 362(17): 1563–1574).

Blood Pressure Trial:
In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (NEJM. 2010; 362: 1575-1585).

EYE Substudy:
Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (NEJM. 2010; 363: 233-244).

MIND Substudy:
Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Lancet Neurol. 2011; 10(11): 969–977).

Additional Details

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