Late changes after a euglycaemic insulin clamp can lead to significant increases in QTcF in healthy subjects

J Taubel1, U Lorch1, D Djumanov1, J Singh1, V Batchvarov2, I Savelieva2, A Camm2. 1Richmond Pharmacology Limited, St George\'s University of London, SW17 0RE, UK, 2St George’s University of London, Cardiovascular Sciences Research Centre, Division of Clinical Sciences, UK

Food alters the QTc and might be an attractive non-pharmacological method of confirming assay sensitivity in Thorough QT (TQT) studies. This idea was recently examined (Taubel et al., 2011) and showed that food shortens QTcF. This is important because previously it has been debated whether euglycaemic hyperinsulinemia can prolong the QTc interval (Gastaldelli et al. 2000). Others have shown that C-peptide can shorten the QT interval (Wahren et al., 2000). Despite these observations, there is a paucity of data when the food effect and QT interval is examined. In this study 32 healthy Caucasian & Japanese subjects were randomised to receive treatment (placebo, insulin euglycaemic clamp, high carbohydrate content breakfast, calorie reduced FDA breakfast, & moxifloxacin) over two periods in a TQT study. Given that insulin was raised to physiological levels comparable to those seen after a meal, whilst the excretion of C-peptide was suppressed, this study revealed that there are late changes after an insulin clamp leading to significant changes in ddQTcF and that raised insulin levels by themselves do not prolong QTc. Notably, the finding that the C-peptide (QT shortening) effect couples with the antagonising (prolongation) effects of glucose is important because it has been known that prolongation of the QT interval has been associated with patients who have insulin-dependent diabetes mellitus (IDDM).

With this in mind and because the 12 lead ECG ddQTcF analysis performed at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours demonstrated an increase in the ddQTcF after the euglycaemic clamp it was decided to investigate the relationship between the time course and ddQTcF using 12 lead Holter analysis for six subjects between the 4 and 6hr time points. Holter analysis was used to determine the time point for the peak ddQTcF. Simultaneously with the acquisition of the standard 10-second 12-lead ECGs (500 samples/second, 5 µV amplitude resolution), 12 lead Holter recordings were acquired in supine position (1000 samples/second, 5 µV resolution). In each Holter recording, the QT interval was measured automatically on lead-specific median beats created from 10-second snapshots at 10-min intervals with manual onscreen over reading of the superimposed median complexes. Specifically, the 2 hour time span was split into 15 minute measurements (4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75Hr).

Using 12 lead Holter analyses this study demonstrated that the maximum QTc prolongation was in fact observed at 5.5hrs i.e. 3.5hrs after the euglycaemic clamp and thereafter decreases steadily at the 5.75hr and 6hr time points. Whilst the precise physiological mechanism remains to be established, late changes in QTc after the euglycaemic clamp might be associated with fluctuating serum potassium levels. Although this idea has been coined by others (Gastaldelli et al. 2000) the precise mechanisms of how fluctuating potassium levels might be implicated in modulating the QT interval after a euglycaemic clamp would require further investigation.