BACKGROUND:Glycaemic dysregulation is associated with clinically diagnosed atrial fibrillation (AF), but prior studies have largely relied on limited monitoring of heart rhythm and glucose levels. We investigated whether periods with higher glucose exposure were associated with AF burden and progression in individuals undergoing long-term continuous monitoring and serial haemoglobin A1c (HbA1c) measurements. METHODS:Post-hoc analysis of 884 LOOP Study participants without diabetes undergoing implantable loop recorder (ILR) screening for AF and repeated HbA1c measurements. AF burden, defined as percentage of time in AF, was calculated in the 60-days prior to blood sampling and analysed in groups by highest HbA1c level and using a two-part mixed-effects model, while AF progression was assessed by cumulative AF duration and burden over time. RESULTS:The dataset combined >1 million days of heart rhythm monitoring (including 34,852 with AF) with 3079 HbA1c measurements. The AF burden was 0.52% [0.09-3.45%], 0.78% [0.25-4.07%], and 4.42% [0.98-13.1%], for HbA1c measurements in the normal (≤38 mmol/mol), prediabetic (39-47 mmol/mol), and diabetic (≥48 mmol/mol) range, respectively. A 1 mmol/mol increase in HbA1c was associated with a 5% relative increase in AF burden (adjusted estimate 1.05 [1.00-1.09], p = 0.039). Participants reaching prediabetes or diabetes accumulated longer AF durations and higher AF burden over time compared to participants with consistently normal HbA1c. CONCLUSION:Higher HbA1c levels were associated with higher AF burden and lower HbA1c levels were associated with lower AF burden and less accumulation of AF over time. TRIAL REGISTRATION:ClinicalTrials.gov, identifier: NCT02036450.

AIMS:To provide a comprehensive overview of the cardiovascular and renal effects of glucose-dependent insulinotropic polypeptide (GIP) by integrating its physiological role with recent human trial data on tirzepatide, the first dual GIP and glucagon-like peptide-1 (GLP-1) receptor agonist. MATERIALS AND METHODS:This narrative review synthesizes key physiological data of native GIP across tissues-especially the heart, vessels, kidney, and adipose tissue-and summarizes clinical evidence from the SUMMIT and the SURPASS programmes. Central to this review is the analysis of the SURPASS-CVOT trial, which compared the cardiovascular protective effects of tirzepatide versus dulaglutide in individuals with type 2 diabetes and established atherosclerotic CV disease. RESULTS:Preclinical data regarding GIP receptor modulation in the cardiorenal district remains controversial, a contention partially reflected in recent clinical evidence. Within the innovative framework of SURPASS-CVOT, tirzepatide established non-inferiority to dulaglutide for 3-point MACE while slowing eGFR decline in participants with high-risk chronic kidney disease. Furthermore, the SUMMIT trial demonstrated that in individuals with obesity and heart failure (HF) with preserved ejection fraction, tirzepatide reduced the composite endpoint of CV death or worsening HF events, regardless of baseline kidney function. Despite these advancements, knowledge gaps persist regarding the potential synergistic cardiorenal benefits of combining dual incretin agonism with sodium-glucose cotransporter-2 inhibitors. CONCLUSION:While adding GIP receptor agonism to GLP-1 receptor agonism clearly improves cardiometabolic risk factors, its precise and independent contribution to long-term CV and renal protection remains to be fully elucidated. Ongoing outcome trials, such as SURMOUNT-MMO and TREASURE-CKD, will provide additional insights into these effects. Furthermore, emerging strategies-including combining GIP receptor antagonism with GLP-1 receptor agonism or moving toward triple agonism-represent promising alternatives to favorably modify the multiple determinants of cardiometabolic risk.

AIMS:To investigate whether plasma glucose decline rates influence cardiac repolarisation, transmural dispersion and counterregulatory hormones in individuals with type 1 diabetes (T1D) with and without good glycaemic control. MATERIALS AND METHODS:In a randomised crossover study, 20 young men with T1D (10 well-regulated (HbA1c ≤53 mmol/mol); 10 dysregulated (HbA1c ≥63 mmol/mol)) underwent two separate glucose clamps involving either a rapid (Clamp-rapid) or slow (Clamp-slow) decline in plasma glucose from hyperglycaemia (baseline) (15 mmol/L) to euglycaemia (5 mmol/L). Changes in cardiac repolarisation (QTc interval), transmural dispersion (measured as the T-peak to T-end interval (Tpe interval)) and counterregulatory hormones were assessed. Study outcomes were primarily compared between clamp days (Clamp-rapid vs. Clamp-slow) and secondarily between subgroups (dysregulated vs. well-regulated). RESULTS:The QTc interval increased by 5 ms from baseline after both rapid and slow glucose declines from hyperglycaemia to euglycaemia, and the ΔQTc interval did not differ between clamp days (mean difference: 0.10 ms [95% confidence interval (CI): -5.20; 4.99], p = 0.970). Accordingly, increases in both the Tpe interval and plasma adrenaline were comparable between clamp days. Subgroup analysis revealed no differences in ΔQTc or ΔTpe intervals between groups; however, after a rapid plasma glucose decline, the plasma adrenaline concentration tended to increase more in the dysregulated group compared to the well-regulated group. CONCLUSION:The plasma glucose decline rate has no clinically relevant effect on cardiac repolarisation, transmural dispersion or sympathoadrenal response in young, otherwise healthy men with T1D. However, individuals with dysregulated T1D may exhibit an altered threshold for sympathoadrenal activation compared to those with well-regulated diabetes.

Introduction The global prevalence of people living with overweight has tripled since 1975 and more than 40% of Danish women enter pregnancy being overweight. With the increasing rates of obesity observed in children, adolescents and adults, there is an urgent need for preventive measures. Risk factors for childhood obesity include maternal overweight or obesity before conception and excessive weight gain during pregnancy. Interventions aimed at modifying maternal lifestyle during pregnancy have demonstrated minimal positive or no impact on the health of the children. The 'healthy lifestyle before and during pregnancy to prevent childhood obesity - the PRE-STORK trial' aims to provide insights into the effect of a lifestyle intervention initiated before conception and continued during pregnancy in women with overweight or obesity, on neonatal adiposity in their children.Methods and analysis In this randomised, two-arm, parallel-group, controlled trial, we will include 360 women with overweight or obesity (aged 18-40; body mass index 25-44 kg/m2) and their partners. The women will be randomised to receive either standard of care or a lifestyle intervention focused on preconception body weight reduction, regular physical exercise, healthy diet and support from a mentor before and during pregnancy. The primary outcome is the difference in neonatal adiposity measured in their children at birth. Children conceived during the trial will constitute a birth cohort, monitoring the effects on their health until the age of 18 years.Ethics and dissemination The trial has been approved by the Regional Committee on Health Research Ethics in the Capital Region of Denmark (identification number H-22011403) and will be conducted in agreement with the Declaration of Helsinki. All results, whether positive, negative and inconclusive, will be disseminated at national or international scientific meetings and in peer-reviewed scientific journals.Trial registration number ClinicalTrials.gov: NCT05578690 (October 2022).

AIMS/HYPOTHESIS:We aimed to examine arrhythmias and hypoglycaemia among individuals with and without diabetes who are receiving haemodialysis and to investigate the association between arrhythmias and hypoglycaemia, hyperglycaemia and glycaemic variability. METHODS:This prospective multicentre cohort study included 70 participants on maintenance haemodialysis (35 with diabetes and 35 without diabetes). We employed implantable cardiac monitors for continuous heart rhythm monitoring in combination with periodic use of continuous glucose monitoring. Logistic-regression-type linear mixed models were used to examine associations between arrhythmias and glycaemic measures. RESULTS:During 18 months of follow-up, clinically significant arrhythmias (bradyarrhythmia and ventricular tachycardia) were identified in 12 (34%) participants with diabetes and 11 (31%) without diabetes. Atrial fibrillation was detected in 13 (37%) participants with diabetes and 14 (40%) without, while other supraventricular tachycardia was detected in seven (20%) and 11 (31%) participants with and without diabetes, respectively. Hypoglycaemia (sensor glucose <3.9 mmol/l) was observed in 27 (77%) participants with diabetes and 32 (91%) without diabetes. Compared with euglycaemia, hypoglycaemia was associated with an increased rate of arrhythmias among participants without diabetes (incidence rate ratio [IRR] 3.13 [95% CI 1.49, 6.55]), while hyperglycaemia (sensor glucose >10.0 mmol/l) was associated with a decreased rate of arrhythmias among participants with diabetes (IRR 0.58 [95% CI 0.37, 0.92]). Glycaemic variability showed no association with arrhythmias regardless of the presence of diabetes. CONCLUSIONS/INTERPRETATION:Arrhythmias and hypoglycaemia were common in those undergoing haemodialysis regardless of diabetes status. Our data suggest a temporal relationship between arrhythmias and glucose level in both individuals with and without diabetes. TRIAL REGISTRATION:Clinicaltrials.gov: NCT04841304.

BackgroundHypoglycemia is common in individuals with type 1 diabetes, especially during exercise. We investigated the accuracy of two different continuous glucose monitoring systems during exercise-related hypoglycemia in an experimental setting.Materials and methodsFifteen individuals with type 1 diabetes participated in two separate euglycemic-hypoglycemic clamp days (Clamp-exercise and Clamp-rest) including five phases: 1) baseline euglycemia, 2) plasma glucose (PG) decline ± exercise, 3) 15-minute hypoglycemia ± exercise, 4) 45-minute hypoglycemia, and 5) recovery euglycemia. Interstitial PG levels were measured every five minutes, using Dexcom G6 (DG6) and FreeStyle Libre 1 (FSL1). Yellow Springs Instruments 2900 was used as PG reference method, enabling mean absolute relative difference (MARD) assessment for each phase and Clarke error grid analysis for each day.ResultsExercise had a negative effect on FSL1 accuracy in phase 2 and 3 compared to rest (ΔMARD = +5.3 percentage points [(95% CI): 1.6, 9.1] and +13.5 percentage points [6.4, 20.5], respectively). In contrast, exercise had a positive effect on DG6 accuracy during phase 2 and 4 compared to rest (ΔMARD = -6.2 percentage points [-11.2, -1.2] and -8.4 percentage points [-12.4, -4.3], respectively). Clarke error grid analysis showed a decrease in clinically acceptable treatment decisions during Clamp-exercise for FSL1 while a contrary increase was observed for DG6.ConclusionPhysical exercise had clinically relevant impact on the accuracy of the investigated continuous glucose monitoring systems and their ability to accurately detect hypoglycemia.

Context Subclinical thyroid dysfunction is a marker for atrial fibrillation (AF) and stroke risk.Objective This study explored the effects of AF screening according to thyroid-stimulating hormone (TSH) levels.Methods An AF screening trial (the LOOP study) was analyzed post hoc according to baseline TSH. The primary outcome was stroke or systemic embolism (SE). Secondary outcomes included major bleeding, all-cause death, and the combination of stroke, SE, and cardiovascular death.Results TSH measurements were available in 6003 of 6004 trial participants, 1500 randomized to implantable loop recorder (ILR) screening for AF and anticoagulation upon detection vs 4503 to usual care; mean age was 74.7 +/- 4.1 years and 2836 (47%) were women. AF detection was approximately triple for ILR vs usual care across TSH tertiles (adjusted P interaction = 0.44). In the first tertile, screening was associated with decreased risk of the primary outcome (hazard ratio [HR] 0.52, 95% CI 0.30-0.90; P = .02) and stroke, SE, or cardiovascular death (HR 0.54, 95% CI 0.34-0.84; P = .006) compared with usual care, while no effect was observed among participants with higher TSH (adjusted P interaction .03 and .01, respectively). There was no effect on other outcomes. Analyses of continuous TSH or excluding those with abnormal TSH or thyroid medication showed similar results.Conclusion AF screening and subsequent treatment was associated with decreased stroke risk among participants with low TSH, though the yield of screening was similar across TSH levels. TSH may be useful as a marker to indicate benefit from AF screening vs overdiagnosis and overtreatment. These findings should be considered exploratory and warrant further study.

CONTEXT:People with type 1 diabetes (T1D) are at increased risk of thrombosis compared to the general population; however, the underlying mechanisms remain unclear. Hypoglycemia induced at rest can induce coagulation activation, but little is known about the hemostatic effects of exercise-related hypoglycemia in people with T1D. OBJECTIVE:We compared hemostatic profiles of individuals with T1D with healthy controls and explored hemostatic effects of hypoglycemia, induced with or without exercise, in participants with T1D. METHODS:Thrombelastography was used for a baseline hemostatic comparison between fifteen men with T1D and matched healthy controls. In addition, the participants with T1D underwent two euglycemic-hypoglycemic clamp days in a randomized, crossover fashion. Hypoglycemia was induced with the participants at rest (Hypo-rest) or during exercise (Hypo-exercise). Thrombelastography provides data on the rate of coagulation activation (R-time), the rate of clot formation (K-time, α-Angle), the maximum clot amplitude (MA), the functional fibrinogen contribution to the clot strength (MA-FF) and the fibrinolysis (LY-30). RESULTS:The T1D group exhibited a faster rate of coagulation activation (shorter R-time) and a faster clot formation (greater α-Angle) compared with the controls. During the clamp experiments, Hypo-exercise induced an increased clot strength (MA) with a mean difference from baseline of 2.77 mm (95% CI, 2.04-3.51) accompanied with a decreased fibrinolysis (LY-30) of -0.45 percentage point (-0.60 to -0.29). Hypo-rest resulted in increased functional fibrinogen (MA-FF) of 0.74 mm (0.13-1.36) along with an increased fibrinolysis (LY-30) of 0.54 percentage point (0.11-0.98). CONCLUSION:Individuals with T1D exhibit a hypercoagulable hemostatic profile compared with healthy controls and exercise-related hypoglycemia may increase the susceptibility to thrombosis via both procoagulant and antifibrinolytic effects.

Mechanical dispersion (MD) describes heterogeneity in ventricular contraction patterns, and myocardial work (MW) indices quantify ventricular performance. Investigating the myocardial and functional response to acute hypoglycemia and hyperglycemia may aid in identifying putative mechanisms linking glycemia and cardiovascular disease (CVD). From echocardiography performed during euglycemic, hyperglycemic and hypoglycemic clamps, we explored the relationship between glycemia and MD and MW indices in individuals with type 1 diabetes, type 2 diabetes and without diabetes. MD was measured by speckle-tracking echocardiography, and MW measures were derived from pressure-strain loop analyses. We analyzed data (mean±SD) from 84 individuals: 20 young individuals with type 1 diabetes (age: 30±8 years); 24 middle-aged individuals with type 1 diabetes (age: 53±12 years); 21 older individuals with type 2 diabetes (63±7 years), and 21 controls (62±8 years). Results for MD and MW indices are illustrated in Figure 1. In conclusion, acute hyperglycemia leads to an energy-effective myocardium with homogeneous left ventricular contractions. Hypoglycemia increases constructive myocardial work, followed by a less energy-efficient myocardium and more heterogeneous left ventricular contractions, perhaps alluding to a possible link between hypoglycemia and CVD. Disclosure C.R.Andreasen: None. A.Andersen: None. P.G.Hagelqvist: None. K.Maytham: None. M.Sengeløv: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. F.J.Olsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. Funding Danish Diabetes Academy (17SA0031406); Novo Nordisk Foundation (16230)

The impact of hypoglycemia, hyperglycemia and glycemic variability on cardiac arrhythmia susceptibility in people with type 1 diabetes is uncertain. We performed a 12-month prospective observational study employing continuous glucose monitoring and implantable loop recorders to investigate potential associations between glycemia and cardiac arrhythmias. Thirty adults with type 1 diabetes ([mean ± SD] age 63 ± 8 years, BMI 26 ± 5 kg/m2, HbA1c 7.3 ± 1.1% [56.9 ± 11.9 mmol/mol]) and without any history of cardiac arrhythmias were included. Daytime and nighttime incidence rate ratios (IRR) of arrhythmias were determined for hypoglycemia (interstitial glucose (IG) < 3.9 mmol/L), hyperglycemia (IG > 10.0 mmol/L), and glycemic variability (standard deviation and coefficient of variation). Hypoglycemia was not associated with an increased risk of cardiac arrhythmias in comparison with euglycemia (IG 3.9 - 10.0 mmol/L) and hyperglycemia. However, during daytime, a trend of increased risk of arrhythmias was observed when comparing hypoglycemia with euglycemia (IRR 1.08 [95% CI 0.99 - 1.18]). Furthermore, during daytime both the occurrence of hyperglycemia and time spent in hyperglycemia within the same hour of an arrhythmia were associated with an increased risk of arrhythmias compared to euglycemia (IRR 2.03 [95% CI 1.21 - 3.40] and IRR 1.07 [95% CI 1.02 - 1.13], respectively). Nighttime hypoglycemia and hyperglycemia were not associated with increased risk of arrhythmias. Increased glycemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during nighttime. In conclusion, daytime hypoglycemia and hyperglycemia may contribute to an increased risk of cardiac arrhythmias compared to euglycemia, in people with type 1 diabetes. No associations were found between glycemic levels and cardiac arrhythmias during nighttime, indicating diurnal differences in arrhythmogenic susceptibility. Disclosure P.G.Hagelqvist: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. A.Andersen: None. K.Maytham: None. C.R.Andreasen: None. S.Engberg: Employee; Novo Nordisk A/S. T.B.Lindhardt: None. J.Forman: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. Funding Novo Nordisk Foundation (28300)

Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell–β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell–β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.

AIMS:To investigate changes in cardiac repolarisation during exercise-related hypoglycaemia compared to hypoglycaemia induced at rest in people with type 1 diabetes. MATERIAL AND METHODS:In a randomised crossover study, 15 men with type 1 diabetes underwent two separate hyperinsulinaemic euglycaemic-hypoglycaemic clamp experiments during Holter-ECG monitoring. One experiment included a bout of moderate-intensity cycling exercise (60 min) along with declining plasma glucose (PG; Clamp-exercise). In the other experiment, hypoglycaemia was induced with the participants at rest (Clamp-rest). We studied QTc interval, T-peak to T-end (Tpe) interval and hormonal responses during three steady-state phases: (i) baseline (PG 4.0-8.0 mmol/L); (ii) hypoglycaemic phase (PG <3.0 mmol/L); and (iii) recovery phase (PG 4.0-8.0 mmol/L). RESULTS:Both QTc interval and Tpe interval increased significantly from baseline during the hypoglycaemic phase but with no significant difference between test days. These changes were accompanied by an increase in plasma adrenaline and a decrease in plasma potassium on both days. During the recovery phase, ΔQTc interval was longer during Clamp-rest compared to Clamp-exercise, whereas ΔTpe interval remained similar on the two test days. CONCLUSIONS:We found that both exercise-related hypoglycaemia and hypoglycaemia induced at rest can cause QTc-interval prolongation and Tpe-interval prolongation in people with type 1 diabetes. Thus, both scenarios may increase susceptibility to ventricular arrhythmias.

Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes (n = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes (n = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a posthoc analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: -4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: -4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by -0.17 nmol/mmol (95% CI: -0.29 to -0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: -0.02 to 0.22)) resulting in a significant between-group difference (p = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a posthoc analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. Clinicaltrials.gov: NCT02890745 and NCT02914691.

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases.

To investigate changes in cardiac repolarization abnormalities (heart rate‐corrected QT [QTc] [primary endpoint], T‐wave abnormalities) and heart‐rate variability measures in people with type 1 diabetes during insulin‐induced hypoglycaemia followed by recovery hyperglycaemia versus euglycaemia.

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)