Veterans Affairs Diabetes Trial - VADT

Description:

Two large recent randomized controlled trials have shown that intensive glucose control in patients with diabetes is not associated with an improvement in cardiovascular (CV) outcomes, compared with standard glucose control. VADT was a similar trial, in which patients with poorly controlled type 2 diabetes were randomized to either intensive glucose control or standard therapy.

Hypothesis:

Intensive glucose control would be associated with a reduction in CV outcomes compared with standard glucose control in patients with poorly controlled type 2 diabetes.

Study Design

Study Design:

Patients Screened: 20,027
Patients Enrolled: 1,791
Mean Follow Up: 7.5 years (median 5.6 years)
Mean Patient Age: 60.4 years
Female: 3

Patient Populations:

  • Inadequate response to maximal doses of an oral agent or insulin therapy

Exclusions:

  • HbA1c <7.5%
  • Occurrence of a CV event within 6 months
  • Advanced congestive heart failure
  • Severe angina
  • Life expectancy <7 years
  • BMI >40
  • Serum creatinine >1.6 mg/dl
  • Alanine aminotransferase (ALT) >3x upper limit of normal

Primary Endpoints:

  • Composite of MI, stroke, death from CV causes, and new or worsening congestive heart failure
  • Surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease, inoperable coronary artery disease, and amputation for ischemic gangrene

Secondary Endpoints:

  • New or worsening angina
  • New transient ischemic attack
  • New intermittent claudication
  • New critical limb ischemia
  • All-cause mortality
  • Microvascular complications including retinopathy, neuropathy, and nephropathy
  • Adverse events, including hypoglycemia

Drug/Procedures Used:

In both study groups, patients with a body mass index (BMI) of 27 or more were started on two oral agents, metformin plus rosiglitazone. Patients with a BMI of <27 were started on glimepiride plus rosiglitazone. Patients in the intensive therapy group were started on maximal doses, and those in the standard-therapy group were started on half the maximal doses.

Before any change in oral medications, insulin was added for patients in the intensive-therapy group who did not achieve a glycated hemoglobin (HbA1c) level of <6% and for those in the standard-therapy group with a level of <9%. Other approved drugs could be used at the discretion of the investigators. The goal for HbA1c was an absolute reduction of 1.5% points in the intensive-treatment arm, compared with the standard-treatment arm.

Concomitant Medications:

Antiplatelet agents (93%), statins (85%)

Principal Findings:

The trial was stratified by current insulin use and prior macrovascular event. A total of 1,791 patients were randomized, 892 to the intensive-therapy arm, and 899 to the standard-therapy arm. Baseline characteristics were fairly similar between the two groups. The baseline HbA1c was 9.4%; the mean duration of diabetes was about 11.5 years. The mean BMI was 31.3. About 40% of patients had a history of a CV event, 72% had a history of hypertension, and about 62% of patients had a history of microvascular disease. Mean low-density lipoprotein, high-density lipoprotein, and triglycerides were 108 mg/dl, 36 mg/dl, and 212 mg/dl, respectively. The baseline creatinine was 1.0 mg/dl.

At the end of 6 months, the mean HbA1c was 6.9% in the intensive-control arm vs. 8.4% in the standard-therapy arm. The difference between the two arms was sustained over 78 months.

There was no difference between the intensive-control and standard-control arms in the incidence of the primary endpoint (any CV event, including myocardial infarction [MI], stroke, CV death, congestive heart failure, surgery for vascular disease, inoperable coronary artery disease, and amputation for ischemic gangrene) (29.5% vs. 33.5%, hazard ratio 0.88, 95% confidence interval 0.74-1.05, p = 0.14). Similarly, there was no difference in the incidence of any of the individual endpoints studied, including death (p = 0.62), CV death (p = 0.26), or MI (p = 0.24). Microvascular events were similar between the two arms, including new-onset retinopathy (42.2% vs. 48.9%, p = 0.27), doubling of serum creatinine (8.8% vs. 8.8%, p = 0.99), and new-onset neuropathy (43.5% vs. 43.8%, p = 0.94). All-cause mortality was 11.4% in the intensive therapy group and 10.6% in the standard therapy group (p = 0.62).

Both symptomatic and asymptomatic hypoglycemia were significantly higher in the intensive-treatment arm compared with standard therapy (1,566 vs. 432 events/100 patient-years, p < 0.0001). Nocturnal hypoglycemia was also more common in the intensive-treatment arm (p < 0.0001).

Interpretation:

The results of the VADT study indicate that intensive glycemic control is not associated with a reduction in macrovascular or microvascular events compared with standard glycemic therapy in patients with poorly controlled type 2 diabetes, with an increase in the incidence of adverse events, primarily due to hypoglycemia.

Although the role of tight glycemic control in the prevention of microvascular complications is well established, its role in the prevention of macrovascular complications is debated. While long-term data from the UKPDS study suggested a reduction in MI and death at 10 years, results from the recently published ADVANCE and ACCORD studies suggested otherwise.

The current study also seems to suggest that macrovascular complications are less preventable with tight glycemic control, and are thus likely a result of other co-existing risk factors such as hypertension and hyperlipidemia in these patients. It, however, cannot be ruled out that long-term follow-up of the current study may show a benefit, similar to the UKPDS trial, where a benefit was noted only after 10 years of follow-up.

The other question that this study raises is whether the mechanism of HbA1c lowering (and glucose control) is as important as its actual reduction. Intravascular ultrasound studies such as PERISCOPE have shown no plaque reversal with glimeperide (one of the medications used in this trial) despite HbA1c lowering. It is thus unknown if choosing different pharmacological agents to improve glycemic control would have been associated with different outcomes.

References:

Duckworth W, Abraira C, Moritz T, et al., on behalf of the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Acute Heart Failure, Hypertension

Keywords: Coronary Artery Disease, Follow-Up Studies, Platelet Aggregation Inhibitors, Hyperlipidemias, Diabetes Mellitus, Type 2, Thiazoles, Risk Factors, Creatinine, Hypoglycemia, Hemoglobin A, Glycosylated, Sulfonylurea Compounds, Metformin, Confidence Intervals, Hypertension, Thiazolidinediones, Myocardial Infarction, Insulin, Stroke, Gangrene, Immunosuppressive Agents, Body Mass Index, Heart Failure, Hypoglycemic Agents, Triglycerides


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