In 2009, the New England Journal of Medicine published results from the Veterans Affairs Diabetes Trial (VADT). The study found that intensive glucose (blood sugar) control in older men with longstanding type 2 diabetes did not significantly reduce their risk of major cardiovascular (CV) events, including heart attack, stroke, and death from CV causes, compared with standard blood sugar control.
Researchers recently reported 15-year follow up results from VADT. They found that intensive blood sugar control did not exert any “legacy effect”: the intensive blood sugar control group did not enjoy CV benefits 15 years after the start of the study.
The VADT study originally enrolled over 1,700 veterans with longstanding type 2 diabetes, who were at high risk of cardiovascular disease, and had poorly controlled blood sugar when they enrolled in the study. At the time of enrollment, study participants had been diagnosed with diabetes for an average of 12 years. Their average A1c level, a measure of average blood sugar levels over the previous two to three months, was 9.4%.
The participants were randomly assigned to either intensive glucose-lowering therapy or usual care for about 5.6 years. At the completion of the study, there was a significant difference in blood sugar control: the average A1c in the intensive treatment group was 6.9%, while the average A1c in the usual care group was 8.4%.
Despite the lower A1c levels, there were no benefits shown from intensive treatment on CV outcomes, which included nonfatal heart attack, nonfatal stroke, new or worsening congestive heart failure, amputation for diabetes-related tissue damage, or death from CV causes.
A follow-up observational study was then undertaken to assess whether intensive treatment during the 5.6-year study period had any long-lasting effects, after the interventions were completed. The 10-year VADT follow up showed some benefits to intensive treatment with regard to CV events. At that time, participants in the intensive treatment group still had lower A1c levels compared to the usual care group, despite the gap of several years since the completion of the study.
However, at the newly published 15-year follow-up, the benefits of intensive control on any of the CV outcomes were lost. By this time, both groups had similar A1c levels of about 8%.
This phenomenon may suggest that to achieve the CV benefits, blood sugar control needs to be maintained and that the short-term tight control, without lasting blood sugar control, may not have long-lasting effects.
The new VADT results add to existing evidence from previous large studies that have failed to show any long-lasting benefits of intensive blood sugar control during observational follow-up. One study, however, did show some beneficial legacy effect. The United Kingdom Prospective Diabetes Study (UKPDS) evaluated intensive treatment versus usual care in adults with newly diagnosed type 2 diabetes. When the UKPDS cohort was evaluated 10 years after the completion of the study, the participants from the intensive treatment arm showed benefits with regard to cardiovascular disease, compared to standard care.
Taken together, the evidence suggests that older adults with longer duration of diabetes and/or multiple coexisting conditions may not benefit from intensive blood sugar control. On the other hand, intensive treatment might be beneficial in younger patients, with shorter duration of diabetes and fewer coexisting medical conditions.
Personalization of goals and treatment regimens that can be maintained safely over the long term by the patient might be the best strategy to lower the risk of cardiovascular disease. As I discussed in a previous blog post, treatment of older adults should consider possible dangers of intensive treatment. For example, intensive blood sugar control can overshoot and lead to hypoglycemia, a potentially dangerous condition in which blood sugar falls too low. Hypoglycemic episodes in older adults are particularly harmful and may negate the possible benefits or tighter diabetes control. In older adults, rather than aiming for tight control, we aim for the best control that can be achieved without increasing the risk of hypoglycemia.
For reducing CV risk, the authors of an editorial that accompanied the NEJM study recommend prioritizing interventions that address other CV risk factors. That includes quitting smoking, and managing blood pressure and cholesterol levels with medication, if needed. Newer classes of diabetes medications, such as sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists appear to have CV benefits and low risk of hypoglycemia, and may be considered as well.
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