Is QT prolongation the key to understanding the effect of intensive glucose control on diabetes mortality?
Intensive glycemic control increases diabetes mortality, as seen in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The risk of severe hypoglycemia is present with intensive glycemic controls. The ACCORD trial evaluated effects on QT prolongation, as QT prolongation in diabetes is a critical risk factor in patients with diabetes and complications. Recent studies have stated that glycemic control can affect cardiac repolarization, which has a massive effect on lethal ventricular arrhythmias. In prior studies that assessed how short-term intensive glycemic control influences heterogeneity of repolarization present in uncontrolled diabetes, no improvement was found other than reporting a decrease in mean HA1c from 10 to 7%. One study found that glycemic variability was linked with QT prolongation and dispersion.
The ACCORD trial’s objective was to evaluate the effects of intensive glycemic control and intensive blood pressure control on the risk of QT prolongation events. The authors of this study “hypothesized that a strategy of intensive glycemic control would be associated with an increased risk of new QT prolongation in ACCORD and that this might explain the increased risk of cardiovascular and all-cause mortality observed in the intensive glycemic control arm.” The study design was a randomized clinical trial analyzing two groups: glycemic control – intensive vs. standard, and blood pressure control – intensive vs. standard. The study also assessed lipid control – simvastatin plus fenofibrate vs. placebo.
The participants were required to have a history of type 2 diabetes, HbA1c ≥ 7.5%, ≥ 40 years old with cardiovascular disease or ≥ 55 years old with atherosclerosis, albuminuria, left ventricular hypertrophy, and dyslipidemia, hypertension, smoking, or obesity. Nine thousand eight hundred eighty-six participants were eligible to complete the study. The primary outcome was the time to first measured QTc as described at a QTc > 460 ms in women or > 450 ms in men.
Using the Kaplan-Meier statistical analysis, the study compared survival free of the incident from QT prolongation in the treatment groups. The log-rank determined the group differences. Cox proportional hazards modeling compared risk of incident QT prolongation as determined from the treatment groups, providing hazard ratios (H.R.) and 95% confidence intervals (CI). Martingale residual plots and ln functions determined the assumption of time-independent proportionality of risks. Using two-sided p-values <0.05 were statistically significant.
QTc prolongation was measured using the QTc Framingham calculation. Of the 10,205 participants enrolled in the study, 316 participants had a prolonged QTc. The baseline QTc prolongation average who did not have a continued baseline QTc was 411 ± 17 ms. As seen at the end of the study, the average QTc among participants was 417 ± 21 ms. The development of QTc prolongation occurred in 634 participants throughout the course. The intensive glycemic control group did not report an increased risk of events in QT prolongation with HR 0.95, 95% CI (0.81-1.11), p-value 0.53. The intensive blood pressure control groups found no evidence of a significant change in risk of prolonged QT with HR 0.84, 95% CI (0.66-1.06), and p-value 0.15.
Studying the effects of intensive glycemic control and blood pressure control in diabetes on QT prolongation is essential, due to the fact of such increased risks of cardiovascular disease in uncontrolled diabetes. The study concluded that intensive glycemic control compared to standard glycemic control did not show a higher risk of the incident in QT prolongation. Intensive blood pressure control compared to standard treatment blood pressure control also did not report a higher risk of incident QT prolongation.
The authors stated that the increased mortality in the intensive glycemic control group is not explained by the increased rate of QT prolongation that leads to lethal ventricular arrhythmias. Limitations of the ACCORD trial were the limitations of examining the effects on the QT interval. There is data suggesting that certain components of the QT interval may be more predictive of the risk of sudden cardiac death than others, such as the T wave onset to T peak component; thus, it is possible that intensive glycemic control may increase the risk of ventricular arrhythmia by increasing T-wave dispersion. Future studies should look at the T wave patterns and include a detailed analysis of the T wave.
- Cardiovascular risk factors in diabetes cause an increased risk of mortality.
- QT prolongation may increase the risk of cardiovascular events in patients with diabetes.
- Intensive glycemic control and blood pressure control did not increase the risk of incident QT prolongation in diabetes patients.
Matthew J. Singleton, Elsayed Z. Soliman, Alain G. Bertoni, S. Patrick Whalen, Prashant D. Bhave, Joseph Yeboah. Effect of Intensive Glycemic and Blood Pressure Control on QT Prolongation in Diabetes: The ACCORD Trial Diabetes Oct 2020,
Tarshay Boyd, PharmD. Candidate, LECOM School of Pharmacy