235-OR: Sustained QTc Prolongation during Recovery from Hypoglycemia in Patients with Type 1 Diabetes
Authors: ANDREASEN CHRISTINE R. , ANDERSEN ANDREAS , HAGELQVIST PER G. , LAURITSEN JULIUS V. , ENGBERG SUSANNE , HOLST JENS J. , PEDERSEN-BJERGAARD ULRIK , KNOP FILIP K. , VILSBØLL TINA 
Published: May 2022

Hypoglycemia and increased glycemic variability have been associated with cardiac arrhythmias and sudden cardiac death. We investigated cardiac repolarization during acute hypoglycemia followed by recovery to hyperglycemia or euglycemia in patients with type 1 diabetes. In a randomized crossover study, patients with type 1 diabetes (N=24, (mean±SD) age 53±years, HbA1c 7.5±0.8% [57.6±8.9 mmol/mol], diabetes duration 23±14 years, BMI 25.7± 3.1 kg/m2) underwent two clamps with three steady-state phases: 1) a hyperinsulinemic-euglycemic phase for 45 minutes, 2) a hyperinsulinemic-hypoglycemic phase for 60 minutes, and 3) a recovery phase in hyperglycemia (clamp A) or euglycemia (clamp B) for 60 minutes. Continuous ECG (Holter) monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. Linear mixed models were used to assess the impact of hypoglycemia and recovery to hyperglycemia vs. euglycemia on cardiac repolarization. Heart rate-corrected QT (QTc) (Fridericia’s formula) progressively increased from baseline (mean (95% CI) , clamp A: 415 msec (409;421) ; clamp B: 418 msec (412;424)) during hypoglycemia on both clamp days (∆mean (95% CI) , clamp A: 21 msec (11;31) ; clamp B: 22 msec (12;31)) . In the recovery phase, QTc remained increased during hyperglycemia and euglycemia (17 msec (11;21) vs. 14 msec (10;20)) with no difference in change between recovery to hyperglycemia compared to euglycemia (3 msec (-6;11) , P=0.5442) . No significant changes from baseline were observed in QTc dispersion (heterogeneity of myocardial repolarization) during hypoglycemia or in the recovery phases. We conclude that clinically significant QTc prolongations during insulin-induced hypoglycemia remain during a 60-minute recovery period independently of recovery to hyperglycemia or euglycemia in patients with type 1 diabetes. Thus, vulnerability for serious cardiac arrhythmias and sudden cardiac death may extend beyond a hypoglycemic event itself.

Disclosure
C.R.Andreasen: None. A.Andersen: n/a. P.G.Hagelqvist: None. J.V.Lauritsen: None. S.Engberg: Employee; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd.

Funding
Danish Diabetes Academy (NNF17SA0031406)