In patients with type 2 diabetes and a history of or high risk for cardiovascular disease, arrhythmias occurred more frequently during periods of hypoglycemia, researchers found.
And the problem appeared to be exaggerated when the hypoglycemia occurred at night, Simon R. Heller, MB BChir, DM, of the University of Sheffield, and colleagues reported in the May issue of Diabetes.
Most hypoglycemic episodes among the 25 patients occurred at night and were asymptomatic. But bradycardia was eight-fold higher during nocturnal hypoglycemia episodes compared with normal glucose periods (incident rate ratio 8.42, 95% CI 1.40-51.0) and atrial ectopic activity was nearly four-fold higher during nighttime low blood sugar episodes (IRR 3.98, 95% CI 1.10-14.40).
Heller said the findings show hypoglycemia is common in type 2 diabetic patients, but often goes unrecognized, even when intensive glucose management is not the goal.
"To see people on normal insulin going to sleep and having 2, 3, and even 4 hours of low glucose values of around 14 mg/dL was surprising, and it was also surprising to see that these people just slept through it," he said. "They were completely unaware it was happening."
Heller said the findings may explain how "silent" hypoglycemia can lead to prolonged, slow heart rates that disturb blood flow to the heart and put vulnerable patients at risk for cardiovascular events.
"Hypoglycemia at night is clearly under-recognized in type 2 diabetes, and while we don't want to overly alarm people, this is something that should be recognized," he said.
Heller added that it may be prudent to recommend nighttime glucose monitoring for at-risk patients and consider switching these patients from human insulin to more modern insulins, which are more expensive but may have a lower risk for causing nocturnal hypoglycemia.
"If these data are confirmed, and it becomes clear that nighttime hypoglycemia is not as innocent as we thought it was, this is something we may need to think about," he said.
Impact on ACCORD?
The results could help solve the mystery of why mortality rates were higher than expected in intensive glucose management trials like ACCORD and NICE-SUGAR.
In 2008, the NIH-funded intensive glucose lowering ACCORD trial was halted early due to an unexpectedly high mortality rate among the enrollees. The overall trial results showed a 22% elevated all-cause mortality and a 35% elevated cardiovascular mortality with the intensive glucose management arm targeting HbA1c of 6.5% versus a standard strategy aiming at 7.0% HbA1c.
Post hoc analyses of ACCORD discounted several potential contributing factors, including rapid HbA1c reduction, higher insulin use, weight gain, and severe hypoglycemia. But Heller told MedPage Today that the analyses would not have included nocturnal hypoglycemic events, because they are not typically measured or even recognized.
Hypoglycemia has been linked to cardiac arrhythmias in type 1 diabetes patients who died unexpectedly in their sleep, and this is what led Heller's group to suspect that unrecognized nighttime low blood sugar may increase cardiovascular disease (CVD) mortality risk among vulnerable type 2 diabetics.
In previous studies, Heller and colleagues demonstrated that experimental hypoglycemia prolongs the QT interval in people with type 1 and type 2 diabetes.
"Since arrhythmias can be triggered by a transient change in sympathovagal balance, it also seems worthwhile exploring the effect of hypoglycemia on autonomic tone," they wrote in the current study.
Continuous ECG, Glucose Monitoring
The study population was made up of 25 patients with type 2 diabetes and a history of CVD who had been on standard (twice a day) insulin treatment for at least 4 years. Patients on QT prolonging drugs, and those with permanent atrial fibrillation or bundle branch block on baseline electrocardiogram, were excluded.
All included patients underwent 5 days of simultaneous ambulatory 12-lead Holter and continuous interstitial glucose (IG) monitoring (CGM) while going about their normal routines and undergoing normal diabetes treatments. The time-synchronized CGM was attached and calibrations were performed at least four times during the study week.
"Mindful of the limitations of CGM, we selected a system that has been reported to follow the descent in blood glucose to the hypoglycemic nadir, with the lowest detection limit of 1.1 mmol/L (20 mg/dL), the researchers wrote. "In published data the mean absolute difference between this CGM system and blood glucose was 0.7 mmol/L (12.7 mg/dL) when CGM glucose was <3.9 mmol/L (70 mg/dL) and the rate of change was between -1 and 1 mg/dL/min. The rate of change of 93% of our hypoglycemic data fell within this limit."
Predictive alarms were turned off, and participants were instructed not to view CGM glucose values except during calibrations. Patients were also asked to keep a record of any symptomatic hypoglycemia. An episode of low IG (<3.5 mmol/L) on CGM without simultaneous self-report of symptoms was considered asymptomatic.
A total of 2,323 hours of valid simultaneous ECG and glucose recordings were obtained from the participants, who were similar in age, body mass index, and prevalence of CVD risk to the ACCORD population with a history of CVD risk.
There were a total of 134 hours of recording at hypoglycemia and 1,258 hours at normal blood sugar (euglycemia), with the remaining outside this range. No fatalities were seen among the participants.
When the researchers analyzed 20 matched day hypoglycemic episodes in 11 patients and 14 matched nocturnal episodes from 10 subjects, there were diurnal differences in the duration and depth of hypoglycemia. The mean duration of daytime episodes was 62 minutes, whereas the mean duration of nocturnal episodes was 170 minutes with a lower glucose nadir (1.9 mmol/L versus 2.8 mmol/L). Three of 34 hypoglycemic episodes were symptomatic.
When the incident rate of arrhythmias during hypoglycemia was compared to euglycemia, the minimum heart rate observed during nocturnal hypoglycemia was 34 bpm, with the longest bradycardia period being 156 consecutive beats. Bradycardia was eight-fold higher and did not occur during the day under either glycemic condition. Atrial ectopic activity was nearly four-fold higher during nocturnal hypoglycemia, but was not significantly different during daytime episodes.
During nocturnal hypoglycemia episodes, the researchers observed a pattern of transient cardio-acceleration with each glucose nadir, followed by a phase of heightened vagal counteraction up to 40 to 50 minutes later than was associated with bradycardia.
"We hypothesize that the occurrence of bradycardia may be linked to increased vagal counteraction after sympathetic neural activation," the researchers wrote. "This view is supported by studies of experimental hypoglycemia with autonomic blockade."
Unclear Clinical Implications
In an accompanying editorial, Simon J. Fisher, MD, PhD, of Washington University St Louis, and colleagues, wrote that despite the interesting findings, the clinical implications of the new research were not entirely clear.
"Although hypoglycemia was common, mostly asymptomatic, and often associated with arrhythmias, it was reassuring that there were no fatalities or adverse clinical outcomes associated with these 'benign' hypoglycemia-induced arrhythmias (although the study size was small)," Fisher and colleagues wrote. "Animal studies, however, show that similar benign cardiac arrhythmias do progress to malignant fatal cardiac arrhythmias during severe hypoglycemia. Thus the authors' foreboding data makes the reader feel uncomfortable when pondering what might have happened if the levels of hypoglycemia had been more severe."
They concluded that additional studies are needed to better understand the hypoglycemia-arrhythmia interaction.
"Given the relatively high incidence of hypoglycemia and associated cardiac arrhythmias in patients observed in this study, along with the increased mortality seen in the ACCORD study, one take-home message for patients and healthcare providers is that target glycemic goals should be individualized and adjusted to avoid severe hypoglycemia and potentially fatal hypoglycemia-induced arrhythmias," they wrote.
From the American Heart Association:
The study was funded by the National Institute of Health Research, U.K.
Heller reported consulting for Abbott, the maker of the FreeStyle Navigator Continuous Glucose Monitoring System used in this study.
Co-authors reported no conflicts of interest.