Congress Reports

MedWire - ADA (New Orleans, LA, USA), June 9, 2009: In an updated analysis of the Veterans Affairs Diabetes Trial (VADT), researchers have identified subgroups of patients who gain cardiovascular (CV) and other benefits from intensive glucose control in comparison with standard therapy. Investigators presented findings from these analyses on the final day of the Annual Meeting of the American Diabetes Association (ADA) 2009.

In the initial report from VADT in 2008, the study authors concluded that there was no benefit in terms of CV events, including death, with intensive glucose control [1]. In contrast with this initial interpretation, VADT investigators now believe that some patients might derive a benefit from intensive therapy, including those who are treated early after a diagnosis of type 2 diabetes, those with elevated levels of high-density lipoprotein (HDL), and those without a history of severe hypoglycemic episodes.

In VADT, 1791 patients (mean age 60.4 years) who had a suboptimal response to therapy for type 2 diabetes were randomly assigned to treatment with intensive or standard glucose control. The goal in the intensive therapy group was an absolute reduction of 1.5% in the HbA1c level in comparison with the standard-therapy group. The primary endpoint was time to the first occurrence of a major CV event, defined as a composite of myocardial infarction (MI), stroke, CV death, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene.

Duration of diabetes, HDL levels, and other predictors of CV outcomes
Dr. William C. Duckworth, Carl T. Hayden VA Medical Center, Phoenix, AZ, USA

In VADT, the mean baseline HbA1c level was 9.4%. After a mean follow-up of 6.25 years, this dropped to 6.9% in the intensive control arm and 8.4% with standard glucose-lowering therapy. In the overall VADT study population, intensive control of glucose had no significant benefit on CV events in comparison with standard glucose control (hazard ratio [HR], 0.88; p=0.14). However, newer subgroup analyses tell a more nuanced story. In this presentation, Dr. Duckworth described subgroups of patients who might benefit from intensive therapy as opposed to standard therapy.

At baseline, the mean duration of diabetes was 11.5 years. If intensive therapy was initiated before disease duration reached 15 years, intensive therapy reduced the risk of CV events. The risk of developing a CV event was reduced by 40% among patients receiving intensive glucose control if treatment started 10-15 years after diagnosis. After the 15-year marker, however, the increased risks associated with intensive therapy outweighed the benefits. The risk of developing a CV event doubled if diabetes had been present for more than 20 years before intensive glucose control was initiated.

The strong interaction between duration of diabetes and risk of CV events in the intensive glucose control group (p<0.0001) must be taken into consideration before initiating intensive therapy, Dr. Duckworth said.

Severe hypoglycemia also influenced CV outcomes in VADT. Regardless of treatment arm, severe hypoglycemic episodes increased the risk of CV events by 88% (HR, 1.88; p=0.04). Even more strikingly, recent hypoglycemic events increased the specific endpoints of CV death more than three-fold (HR, 3.72; p=0.01) and increased the risk of all-cause mortality more than six-fold (HR, 6.37; p=0.0001). Given its status as a major risk factor, the presence of severe hypoglycemia should influence treatment goals and strategies, Dr. Duckworth said.

HDL levels also strongly influenced the primary endpoint. Patients with higher HDL levels during the trial had a significantly low-risk of CV events, particularly CV death. For every 10 mg/dL increase in HDL above baseline, patients experienced an 80% decrease in the risk of CV events, including a 55% decrease in all-cause mortality (p=0.01). This underscores the importance of addressing non-glucose CV risk factors, including HDL, in an overall effort to improve the CV risk profiles of patients with type 2 diabetes.

In summary, this updated analysis from VADT showed that several baseline factors interacted with the treatment groups to influence the risk of CV events, including the duration of diabetes, HDL levels, and severe hypoglycemia. Therefore, these factors should be taken into consideration when planning a treatment strategy for patients with type 2 diabetes.

Severe hypoglycemia increases CV morbidity, mortality, and all-cause death
Dr. Stephen N. Davis, Vanderbilt University, Nashville, TN, USA

In this presentation, Dr. Davis focused more closely on the interactions among hypoglycemia, treatment arms, and outcomes in VADT. For example, he found that severe hypoglycemia occurred at a significantly higher rate in the intensive therapy group (approximately 30 episodes per 100 patient-years) than it did in the standard therapy group (approximately 10 episodes per 100 patient-years) (p<0.001).

In the intensive therapy group, lower HbA1c levels, longer duration of disease, and higher body mass index (BMI) were associated with increased rates of severe hypoglycemia. Irrespective of treatment group, severe hypoglycemia was associated with elevated CV risk. Episodes of severe hypoglycemia were significantly increased prior to a primary outcome event, CV death, or all-cause death (p<0.001). In addition, there was a trend toward severe hypoglycemia occuring more commonly prior to a first MI (p=0.08).

The risks related to severe hypoglycemia were significantly increased in the standard therapy group in comparison with the intensive therapy group. For example, severe hypoglycemia had a greater association with CV death and MI in the standard group than it did in the intensive group (p<0.01).

Severe hypoglycemia seemed to accelerate all-cause mortality in the standard therapy group relative to the intensive therapy group. Among patients who died, the median time from a severe hypoglycemia episode to all-cause death in the standard and intensive arms was 6 months and 17 months, respectively.

Dr. Davis found no evidence of a protective HbA1c threshold above which severe hypoglycemia did not occur. In fact, there was a trend toward an increased incidence of severe hypoglycemia with elevated HbA1c levels, and several episodes of severe hypoglycemia were reported in patients with HbA1c levels of 9.0% and higher. Overall, these findings underscore the importance of preventing episodes of severe hypoglycemia, regardless of treatment strategy.

References

1. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.