Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Abstract

Introduction: High spontaneous activity of the renin–angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function during hypoglycaemia. Methods: Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps. Results: Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan was observed. Conclusion: In conclusion candesartan has no effect on cerebral function during mild experimental hypoglycaemia in subjects with type 1 diabetes and high RAS activity. Candesartan may reduce glucose utilisation or increase endogenous glucose production during hypoglycaemia.

Association of hypoglycaemia and risk of cardiac arrhythmia in patients with diabetes mellitus: A systematic review and meta‐analysis

“…Our initial search yielded 4625 citations, of which 67 full texts were assessed for eligibility (Figure ). After examination, 24 publications from 21 studies were considered eligible . Duplicate publications of 3 studies were identified .…”

“…A total of 8 studies had an observational design, reporting outcomes among participants with T1DM (n = 5), with T2DM (n = 2) or with both (n = 1) . The remaining 12 studies involved experimentally induced hypoglycaemia in participants with T1DM (n = 6), with T2DM (n = 5) or with both (n = 1) . The definition of hypoglycaemia varied across studies.…”

“…A total of 17 studies reported outcome data for QTc. As two of these studies reported mean change between the conditions, as opposed to absolute mean values, random effects meta‐analysis was possible for only 15 studies . The two studies excluded from the meta‐analysis reported a significant increase in QTc length during hypoglycaemia ( P < .05).…”

Hypoglycaemia and cardiac arrhythmias in diabetes

“…23–33 In studies applying the hyperinsulinaemic hypoglycaemic clamp, QTc interval prolongation is an almost consistent finding in patients with type 1 diabetes and type 2 diabetes, respectively, as well as healthy control subjects. 23–31 QTc interval has previously been demonstrated to be a predictor of cardiovascular mortality and all-cause mortality in patients with diabetes 34,35 and QTc interval prolongation increases the risk of developing ventricular arrhythmias. 36 However, the magnitude of QTc interval prolongation during experimental hypoglycaemia varies with the applied method of correcting for heart rate.…”

“…The electrocardiographic changes in humans during hypoglycaemia have been explored in several studies employing experimental, insulin-induced hypoglycaemia. 23–33 In studies applying the hyperinsulinaemic hypoglycaemic clamp, QTc interval prolongation is an almost consistent finding in patients with type 1 diabetes and type 2 diabetes, respectively, as well as healthy control subjects. 23–31 QTc interval has previously been demonstrated to be a predictor of cardiovascular mortality and all-cause mortality in patients with diabetes 34,35 and QTc interval prolongation increases the risk of developing ventricular arrhythmias.…”