Insulin at normal physiological levels does not prolong QTc interval in thorough QT studies performed in healthy volunteers.
Summary of "Insulin at normal physiological levels does not prolong QTc interval in thorough QT studies performed in healthy volunteers."
Food is known to shorten the QTc (QTcI and QTcF) interval and has been proposed as a non-pharmacological method of confirming assay sensitivity in Thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C-peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QTc interval, whilst C-peptide has been reported to shorten the QTc interval. Currently there is limited information on the effects of insulin and C-peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C-peptide on the QTc interval under the rigorous conditions of a TQT study.
32 healthy male and female, Caucasian and Japanese subjects were randomised to receive six treatments: 1) placebo, 2) insulin euglycaemic clamp, 3) carbohydrate rich 'continental' breakfast, 4) calorie reduced 'American' FDA breakfast, 5) moxifloxacin without food, and 6) moxifloxacin with food. Measurements of ECG intervals were performed automatically with subsequent adjudication in accordance with the ICH E14 guideline and relevant amendments.
No effect was observed on QTcF during the insulin euglycaemic clamp period (maximal shortening of QTcF by 2.6 ms, not significant). Following ingestion of a carbohydrate rich 'continental' breakfast or a calorie reduced 'American' FDA standard breakfast, a rapid increase in insulin and C-peptide concentrations were observed. Insulin levels showed a peak response after the 'continental' breakfast observed at the first measurement time point (0.25 hours) followed by a rapid decline. Insulin levels observed with the 'American' breakfast were approximately half of those seen with the 'continental' breakfast and showed a similar pattern. C-peptide levels showed a peak response at the first measurement time point (0.25 hours) with a steady return to baseline at the 6 hour time point. The response to the 'continental' breakfast was approximately double that of the 'American' FDA breakfast. A rapid onset of the effect on QTcF was observed under 'continental' breakfast with shortening by > 5 ms in the time interval from 1 to 4 hour. Under the 'American' FDA breakfast, a similar but smaller effect was seen.
The findings of this study demonstrate that there was no change in QTc during the euglycaemic clamp. Given that insulin was raised to physiological levels comparable to those seen after a meal, whilst the release of C-peptide was suppressed, insulin appears to have no effect on the QTc interval in either direction. The results suggest a relationship exists between the shortening of QTc and C-peptide levels and indicate that glucose may have a QTc prolonging effect, which will require further research.
Richmond Pharmacology Ltd., St George's University of London, Cranmer Terrace, London, United Kingdom.
This article was published in the following journal.
Name: British journal of clinical pharmacology
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22775199
- DOI: http://dx.doi.org/10.1111/j.1365-2125.2012.04376.x
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