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Intensive glycemic control and cardiovascular events: an update

VA Diabetes Trial
Similar to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trials, the question of whether intensive glycemic control in patients with type 2 diabetes reduces cardiovascular disease (CVD) events was evaluated in the Veterans Affairs Diabetes Trial (VADT).^1,2,3 This randomized controlled, open-label study included patients who were 41 years or older with a glycated hemoglobin (A1C) level ≥ 7.5% on a maximum dose of at least 1 oral agent and/or daily insulin injections. Selected exclusion criteria were renal or liver dysfunction, a CVD event within the past 6 months, Class III or IV angina or heart failure, and life expectancy less than 8 years. Of 1791 patients, 892 were randomized to intensive treatment and 899 to standard treatment and stratified according to study site, previous occurrence of a CVD event, and current insulin use. The trial had a 2-year data accrual period and a 5-year follow up period. The target A1C for intensive treatment was to achieve an absolute difference of 1.5 percentage points from the standard treatment group (≤ 6% for the intensive group; 8%-9% for the standard group). All patients entering the intensive treatment group on oral agents alone received rosiglitazone 4 mg twice daily and maximum doses of either metformin or glimepiride depending on their body mass index (BMI); obese patients who had a BMI of 27 mg/m² or greater received metformin, and those with a lower BMI received glimepiride. Insulin was added to the oral regimen if necessary. Patients entering the intensive treatment group already on insulin had their regimens intensified to achieve the desired targets. Patients in the standard treatment group received similar oral and/or insulin drug therapy as the intensively treated patients; however, lower doses were used. Both treatment groups had other cardiovascular risk factors managed according to guidelines, which included a blood pressure goal of < 130/80 mm Hg, low density lipoprotein (LDL) goal of < 100 mg/dL and triglyceride (TG) goal of < 200 mg/dL, use of low dose aspirin (81 to 325 mg), and counseling on lifestyle modification and smoking cessation. The primary outcome was the time to first occurrence of a CVD event which included myocardial infarction (MI), stroke, death from cardiovascular causes, new or worsening heart failure, surgical intervention for cardiac, cerebrovascular or peripheral vascular disease, inoperable coronary artery disease and amputation for ischemic gangrene. Microvascular complications and other cardiovascular events were the secondary outcomes.

Results
As would be expected in a veteran population, approximately 97% of patients were male.³ The mean age of patients was 60.4 years with a mean duration of diabetes of 11.5 years and a mean BMI of 31.3. Mean baseline A1C was 9.4%, and 52% of patients were receiving insulin at baseline. At the end of follow-up (mean duration of 6 years), both groups achieved goal mean blood pressure, LDL, and TG levels. Glycated hemoglobin values stabilized after 6 months of therapy at a median level of 6.9% in the intensive group and 8.4% in the standard group. Aspirin use increased similarly in both groups, as did smoking cessation. Compared to standard treatment, intensive treatment led to statistically significant increases in mean body weight (223 lbs vs. 232 lbs, p=0.01) and mean BMI (32.3 kg/m2 vs. 33.8 kg/m2, p=0.01).

No statistically significant difference was observed in the 6-year event rate of the primary outcome between the intensive treatment group (0.66) and the standard treatment group (0.70) (hazard ratio 0.88; 95% confidence interval [CI], 0.74 to 1.05; p=0.14).³ Two hundred sixty four events occurred in the standard group compared to 235 events in the intensive group. Use of insulin at baseline or a previous CVD event did not influence the outcome of either treatment. The only microvascular outcome that improved with intensive treatment compared to standard treatment was worsening of albumin excretion (p=0.05). Although not statistically significant there were a greater number of cardiovascular deaths in the intensive group compared to the standard group (40 vs. 30, respectively) and a greater number of sudden deaths (11 vs. 4, respectively). Hypoglycemia occurred more frequently with intensive treatment and was documented as a serious adverse event in 76 (8.5%) of 892 intensively treated-patients compared to 28 (3.1%) of 899 patients receiving standard treatment (p=0.000). Dyspnea occurred significantly more frequently with intensive treatment compared to standard treatment (11% vs, 7.2%, respectively, p=0.006).

Discussion
In the ACCORD trial, the composite primary endpoint of macrovascular events was not significantly different between the intensive and standard treatment groups.¹ In fact, death from CVD or any cause was significantly higher in the intensive group, which led to early termination of the trial. In the ADVANCE trial, the composite primary endpoint of macrovascular and microvascular events was significantly lower in the intensive control group compared to the standard control group.² When evaluated separately, the main reason for the reduction in the primary endpoint was the decrease in microvascular events, particularly new or worsening nephropathy, in the intensive therapy group.

Similar to results of the recently conducted ACCORD and ADVANCE trials, intensive treatment of type 2 diabetes in the VADT did not lead to a significant reduction in CVD events compared to standard treatment. Although the ACCORD trial was terminated early due to an increase in mortality with intensive treatment, a subgroup analysis of intensively treated patients with no previous CVD events and a baseline A1C of <8% demonstrated significant reduction in CVD events.¹ Post hoc analyses of the VADT results have also suggested lower CVD events in patients with a shorter duration of diabetes at randomization.⁴ Additionally, for patients receiving standard treatment, previous hypoglycemic episodes appeared to be associated with increased mortality.

Two older, pivotal trials, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) also compared microvascular and CVD outcomes of intensive treatment of type 1 and newly diagnosed type 2 diabetes, respectively.^5-7 After an average duration of 6.5 years, intensive treatment of type 1 diabetes (average A1C of 7.2%) in the DCCT led to a 60% reduction in retinopathy, nephropathy, and neuropathy, but no significant difference in cardiovascular events.⁵ However, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a follow up study of DCCT patients 10 years after treatment groups reached similar A1C levels demonstrated a 57% reduction in nonfatal MI, stroke, or CVD related death in patients who had previously received intensive treatment compared to those who had received standard treatment (p=0.02).⁸ In type 2 diabetes, intensive treatment (median A1C of 7%) for an average of 10 years in the UKPDS study led to a 25% reduction in the overall microvascular complication rate and a nonsignificant 16% decrease in cardiovascular events.^6,7 A 10-year follow up study of UKPDS patients demonstrated a 15% reduction in MI (p=0.01) for patients who received previous intensive glycemic control with a sulfonylurea or insulin as initial therapy and a 33% reduction in MI (p=0.005) for patients with previous intensive control with metformin as initial therapy compared to those who received conventional treatment.⁹

Recommendations
Based on the results of these various studies, the American Diabetes Association (ADA) in conjunction with the American Heart Association (AHA) and the American College of Cardiology (ACC) has published a position statement on intensive glycemic control and CVD events.⁴ According to the statement, the subgroup analyses of recent studies and data from the follow up studies of DCCT and UKPDS, suggest that intensive glycemic control early in the course of diabetes in patients without established CVD can help to reduce future CVD events. Intensive glycemic control in advanced diabetes and established CVD, on the other hand, may not play a role in prevention of future CVD events. The statement provides the following guidelines for clinical practice:

These guidelines differ from previous recommendations in that specific populations have been identified in which intensive glycemic therapy may be beneficial or potentially harmful in terms of prevention of macrovascular disease. The recommendations, similar to previous guidelines, continue to support management of other CVD risk factors such as blood pressure, cholesterol, smoking cessation, and use of antiplatelet therapy as the primary means to reduce CVD risk in patients with diabetes.

Clinicians should strive for intensive glycemic control early in the course of diabetes in patients to prevent microvascular and macrovascular complications. However, intensive glycemic control may be less beneficial and potentially, harmful, in patients with long standing diabetes, significant hypoglycemia, and other serious comorbidities.

References