Insulin at normal physiological levels does not prolong QT(c) interval in thorough QT studies performed in healthy volunteers

Abstract

Aims: Food is known to shorten the QT(c) (QT(c)I and QT(c)F) 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 QT(c) interval, whilst C-peptide has been reported to shorten the QT(c) 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 QT(c) interval under the rigorous conditions of a TQT study.

Methods: Thirty-two healthy male and female, Caucasian and Japanese subjects were randomized 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.

Results: No effect was observed on QT(c)F during the insulin euglycaemic clamp period (maximal shortening of QT(c) F 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 concentrations showed a peak response after the 'continental' breakfast observed at the first measurement time point (0.25 h) followed by a rapid decline. Insulin concentrations observed with the 'American' breakfast were approximately half of those seen with the 'continental' breakfast and showed a similar pattern. C-peptide concentrations showed a peak response at the first measurement time point (0.25 h) with a steady return to baseline at the 6 h time point. The response to the 'continental' breakfast was approximately double that of the 'American' FDA breakfast. A rapid onset of the effect on QT(c) F was observed with the 'continental' breakfast with shortening by >5 ms in the time interval from 1 to 4 h. After the 'American' FDA breakfast, a similar but smaller effect was seen.

Conclusions: The findings of this study demonstrate that there was no change in QT(c) during the euglycaemic clamp. Given that insulin was raised to physiological concentrations comparable with those seen after a meal, whilst the release of C-peptide was suppressed, insulin appears to have no effect on the QT(c) interval in either direction. The results suggest a relationship exists between the shortening of QT(c) and C-peptide concentrations and indicate that glucose may have a QT(c) prolonging effect, which will require further research.

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Average change from baseline of insulin, glucose and C-peptide following carbohydrate rich ‘continental’ breakfast (A), calorie reduced ‘American’ FDA breakfast (B), euglycaemic insulin clamp (C) and placebo (D). , C-peptide; , Glucose; , Insulin

Figure 2

Average change from baseline on QTcF following euglycaemic clamp (A), carbohydrate rich ‘continental’ breakfast (B), calorie reduced ‘American’ FDA breakfast (C) compared with placebo. Effect of 400 mg moxifloxacin in fasted state on QTcF (D)

Figure 3

Effect on heart rate with 95% CI on insulin euglycaemic clamp (A), carbohydrate rich ‘continental’ breakfast (B), calorie reduced ‘American’ FDA breakfast (C). Effect of 400 mg moxifloxacin (fasted state) on heart rate (D)

Figure 4

Plot of ΔΔQTcF (ms) against change from time matched placebo of insulin (A), C-peptide (B) and glucose (C) concentration. The solid black lines give the regression lines for insulin after the correction for glucose (A), C-peptide after correction for glucose (B) and for glucose after the correction for C-peptide (C), which are taken as the mean values across the data. The yellow area is the corresponding 95% CI. (A) The grey lines give the predictions for maximum and minimum mean glucose seen over time (change from placebo). The dashed line gives the regression without correction for glucose. (B) The grey lines give the predictions for the glucose concentration seen under placebo and for the maximum mean change of glucose across all time points in the carbohydrate-rich breakfast condition, which occurred at 15 min. The dashed line gives the regression line obtained for C-peptide without correction for glucose. (C) The grey lines give the predictions for the C-peptide level seen under placebo and for the maximum mean change of C-peptide across all time points in the carbohydrate-rich breakfast condition, which occurred at 30 min. The dashed line gives the regression line obtained for glucose without correction for C-peptide. The dotted black line gives the relationship between change of glucose from time matched placebo and ΔΔQTcF established under the euglycaemic clamp. (A) Is based on data obtained under the euglycaemic clamp (time points up to 1.5 h), (B) and (C) are based on all time points of all three regimens (euglycaemic clamp, carbohydrate rich ‘continental’ breakfast and calorie reduced ‘American’ FDA breakfast)

Figure 5

Change in ΔΔQTc (ms) as a function of glucose (mmol ml−1) and C-peptide (ng ml−1). The dashed blue plane shows a concentration dependent shortening with C-peptide and prolongation with glucose