Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration.

INTRODUCTION: Oral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave. METHODS: Part A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF). RESULTS: All subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure-response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms. CONCLUSION: This QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02911870.

Medications that are taken orally can be broken down by acid in the stomach before they are absorbed and therefore be less effective. Oral semaglutide is a novel type 2 diabetes medication that is formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which helps to protect against semaglutide degradation in the stomach. Regulatory authority guidelines recommend that new therapies should be tested for prolongation of the QT interval, an important part of the heart's electrical cycle. A previous trial demonstrated that semaglutide alone, which is currently available as an injectable diabetes therapy, did not prolong the QT interval when given in doses higher than those used in patients. Therefore, the current trial was conducted to assess whether the SNAC component of oral semaglutide has any relevant prolonging effect on the QT interval. Following regulatory guidelines for trials evaluating prolongation of the QT interval, the first part of the trial aimed to find a suitably high dose of SNAC. The second part of the trial aimed to confirm that SNAC does not prolong the QT interval. The results of this trial demonstrated that a 3.6 g dose of SNAC, which is 12-fold higher than the amount contained in oral semaglutide, does not prolong the QT interval. The safety and tolerability of SNAC 1.2 g, 2.4 g and 3.6 g were assessed in this trial and no concerns were identified. These results, taken alongside those of the previous QT interval study with subcutaneous semaglutide, indicate no relevant effect of oral semaglutide on the QT interval.

Nocturnal Heart Rate and Cardiac Repolarization in Lowlanders With Chronic Obstructive Pulmonary Disease at High Altitude: Data From a Randomized, Placebo-Controlled Trial of Nocturnal Oxygen Therapy.

Background: Chronic obstructive pulmonary disease (COPD) is associated with cardiovascular disease. We investigated whether sleeping at altitude increases nocturnal heart rate (HR) and other markers of cardiovascular risk or arrhythmias in lowlanders with COPD and whether this can be prevented by nocturnal oxygen therapy (NOT). Methods: Twenty-four COPD patients, with median age of 66 years and forced expiratory volume in 1 s (FEV1) 55% predicted, living <800 m underwent sleep studies at Zurich (490 m) and during 2 sojourns of 2 days each at St. Moritz (2,048 m) separated by 2-week washout at <800 m. During nights at 2,048 m, patients received either NOT (2,048 m NOT) or ambient air (2,048 m placebo) 3 L/min via nasal cannula according to a randomized, placebo-controlled crossover trial. Sleep studies comprised ECG and pulse oximetry to measure HR, rhythm, HR-adjusted QT interval (QTc), and mean oxygen saturation (SpO2). Results: In the first nights at 490 m, 2,048 m placebo, and 2,048 m NOT, medians (quartiles) of SpO2 were 92% (90; 94), 86% (83; 89), and 97% (95; 98) and of HR were 73 (66; 82), 82 (71; 85), and 78 bpm (67; 74) (P < 0.05 all respective comparisons). QTc increased from 417 ms (404; 439) at 490 m to 426 ms (405; 440) at 2,048 m placebo (P < 0.05) and was 420 ms (405; 440) at 2,048 m NOT (P = NS vs. 2,048 m placebo). The number of extrabeats and complex arrhythmias was similar over all conditions. Conclusions: While staying at 2,048 m, lowlanders with COPD experienced nocturnal hypoxemia in association with an increased HR and prolongation of the QTc interval. NOT significantly improved SpO2 and lowered HR, without changing QTc. Whether oxygen therapy would reduce HR and arrhythmia during longer altitude sojourns remains to be elucidated.

Influence of cardiac autonomic neuropathy on cardiac repolarisation during incremental adrenaline infusion in type 1 diabetes.

AIMS/HYPOTHESIS: We examined the effect of a standardised sympathetic stimulus, incremental adrenaline (epinephrine) infusion on cardiac repolarisation in individuals with type 1 diabetes with normal autonomic function, subclinical autonomic neuropathy and established autonomic neuropathy. METHODS: Ten individuals with normal autonomic function and baroreceptor sensitivity tests (NAF), seven with subclinical autonomic neuropathy (SAN; normal standard autonomic function tests and abnormal baroreceptor sensitivity tests); and five with established cardiac autonomic neuropathy (CAN; abnormal standard autonomic function and baroreceptor tests) underwent an incremental adrenaline infusion. Saline (0.9% NaCl) was infused for the first hour followed by 0.01 µg kg-1 min-1 and 0.03 µg kg-1 min-1 adrenaline for the second and third hours, respectively, and 0.06 µg kg-1 min-1 for the final 30 min. High resolution ECG monitoring for QTc duration, ventricular repolarisation parameters (T wave amplitude, T wave area symmetry ratio) and blood sampling for potassium and catecholamines was performed every 30 min. RESULTS: Baseline heart rate was 68 (95% CI 60, 76) bpm for the NAF group, 73 (59, 87) bpm for the SAN group and 84 (78, 91) bpm for the CAN group. During adrenaline infusion the heart rate increased differently across the groups (p = 0.01). The maximum increase from baseline (95% CI) in the CAN group was 22 (13, 32) bpm compared with 11 (7, 15) bpm in the NAF and 10 (3, 18) bpm in the SAN groups. Baseline QTc was 382 (95% CI 374, 390) ms in the NAF, 378 (363, 393) ms in the SAN and 392 (367, 417) ms in the CAN groups (p = 0.31). QTc in all groups lengthened comparably with adrenaline infusion. The longest QTc was 444 (422, 463) ms (NAF), 422 (402, 437) ms (SAN) and 470 (402, 519) ms (CAN) (p = 0.09). T wave amplitude and T wave symmetry ratio decreased and the maximum decrease occurred earlier, at lower infused adrenaline concentrations in the CAN group compared with NAF and SAN groups. AUC for the symmetry ratio was different across the groups and was lowest in the CAN group (p = 0.04). Plasma adrenaline rose and potassium fell comparably in all groups. CONCLUSIONS/INTERPRETATION: Participants with CAN showed abnormal repolarisation in some measures at lower adrenaline concentrations. This may be due to denervation adrenergic hypersensitivity. Such individuals may be at greater risk of cardiac arrhythmias in response to physiological sympathoadrenal challenges such as stress or hypoglycaemia.

Potassium dynamics are attenuated in hyperkalemia and a determinant of QT adaptation in exercising hemodialysis patients.

Disturbances in plasma potassium concentration (pK) are well known risk factors for the development of cardiac arrhythmia. The aims of the present study were to evaluate the effect of hemodialysis on exercise pK dynamics and QT hysteresis, and whether QT hysteresis is associated with the pK decrease following exercise. Twenty-two end-stage renal disease patients exercised on a cycle ergometer with incremental work load before and after hemodialysis. ECG was recorded and pK was measured during exercise and recovery. During exercise, pK increased from 5.1 ± 0.2 to 6.1 ± 0.2 mM (mean ± SE; P < 0.0001) before hemodialysis and from 3.8 ± 0.1 to 5.1 ± 0.1 mM (P < 0.0001) after hemodialysis. After 2 min of recovery, pK had decreased to 5.0 ± 0.2 mM and 4.1 ± 0.1 mM (P < 0.0001) before and after hemodialysis, respectively. pK increase during exercise was accentuated after hemodialysis. The pK increase was negatively linearly correlated with pK before exercise (ß = -0.21, R(2) = 0.23, P = 0.001). QT hysteresis was negatively linearly correlated with the decrease in pK during recovery (ß = -28 ms/mM, R(2) = 0.36, P = 0.006). Thus, during recovery, low pK was associated with relatively longer QT interval. In conclusion, new major findings are an accentuated increase in pK during exercise after hemodialysis, an attenuated increase in pK in hyperkalemia, and an association between pK and QT interval adaptation during recovery. The acute pK shift after exercise may modulate QT interval adaptation and trigger cardiac arrhythmias.