Evidence for Lack of a Glucose-Control Legacy Effect

Intensive glycemic control shows benefits with time; however, evidence is showing this glucose-control legacy effect may wear off.

Previously the Veterans Affairs Diabetes Trial (VADT) found modest reduction in cardiovascular events with improved glucose control. The modest reduction was found to be insignificant, but a 10-year follow-up, in contrast, showed a positive benefit regarding cardiovascular events.

The Veterans Affairs Diabetes Trial follow-up study (VADT-F) wanted to assess “long-term consequences of intensive glycemic control on cardiovascular disease outcomes, quality of life, and mortality and to assess legacy effects.” For 6 years, 1,791 military veterans with type 2 diabetes received either intensive (HbA1c > 1.5 percentage points lower than standard group) or standard glucose control (HbA1c between 8 to 9%). Other cardiovascular disease risk factors were also aggressively treated. After a median of 5.7 years of therapy, the patients underwent an observational follow-up. Data was collected from 4 national sources and self-administered surveys were given annually to report major events from the past year. The first major cardiovascular event was considered the primary outcome and death from any cause was considered a secondary outcome. Thirdly, they also recorded hospitalizations.

Kaplan-Meier survival curves were used to analyze the intention-to-treat. To determine effects of HbA1c on the primary cardiovascular disease outcome and on the treatment effects, Cox proportional-hazards models were used to estimate hazard ratios. To assess diversity within the treatment effects in terms of the primary and any major diabetes outcome, three variables were prespecified, “duration of diabetes, baseline cardiovascular risk, and history of cardiovascular disease.” Hospitalizations were analyzed using a negative binomial regression. And lastly, to account for missing data of covariates, the researchers carried the most recent value forward.

During treatment, the intensive-therapy group had a median HbA1c of 6.9%. Over 5.6 years, a moderate separation of 1.5 percentage points of HbA1c was seen between the treatment groups. With time, after the trial, the separation seen reduced until both groups had a similar HbA1c of ~8%. The median follow-up was 13.6 years; at this time, researchers found there was a 9% lower risk of the primary cardiovascular disease outcome in the intensive-therapy group, but this decreased risk was found to be nonsignificant (P = 0.23). Similarly, the intensive-therapy group, compared to the standard therapy group, had a lower risk of any major diabetes event (HR: 0.90) and death from cardiovascular causes (HR: 0.94), but these were also found to be nonsignificant.

Furthermore, at a median follow-up of 15 years, those who received intensive treatment had no evidence of shorter time to death nor improved quality-of-life scores compared to those who received standard treatment. There was no evidence of variation between treatment effects across the three pre-specified risk factors.

When comparing the event rates of major outcomes during and after the VADT, no benefit was found regarding any major outcome during the observational follow-up period. However, when assessing the treatment effect before and after the two groups reached similar HbA1c, the intensive-therapy group had a 17% lower risk of primary cardiovascular events than the standard-therapy. This decrease in risk was seen when the separation of the glycated hemoglobin curves between each group was present. Once the separation diminished, a higher risk of major cardiovascular events was then seen in the intensive-therapy group. After adjustment for the difference in glucose control, the difference in risk of cardiovascular disease was eliminated. The authors were left to believe their data supports the lack of a glucose-control legacy effect.

In conclusion, intensive glucose lowering treatment seems to have no significant “glucose-control legacy” effect in lowering the risk for major cardiovascular events, compared to standard treatment, after 15 years. With that, as previously stated, there were no benefits seen regarding mortality, the incidence of hospitalizations, nor difference in quality-of-life. However, during the years of separation of the glycated hemoglobin curves, there was a significantly lower risk of major cardiovascular events. With the loss of separation of the curves, the cardiovascular benefits diminished and there was no evidence proving a beneficial legacy effect after loss of the intense glucose control. While patients were only treated for 5.6 years, it would be interesting to examine the effects of a longer treatment time in regards to greater long-term benefits. Future studies involving randomized controlled trials would be able to give a more robust significance.

Practice Pearls:

• In patients with diabetes, intensive glycemic control to target is not only important, but keeping them at a lower HbA1c may help maintain cardiovascular improvements.
• Patients should be assessed before initiation of intensive glycemic therapy to determine if the benefits outweigh the risks of hypoglycemic events and weight gain.
• Other interventions to reduce cardiovascular risk should be implemented in patients with diabetes with established cardiovascular risks for added benefits.

Reference for “Evidence for Lack of a Glucose-Control Legacy Effect”:

Reaven, Peter, et al. Intensive Glucose Control in Patients with Type 2 Diabetes – 15-Year Follow-up. The New England Journal of Medicine. 2019 June 6.

Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate