No QTc Prolongation with Semaglutide: A Thorough QT Study in Healthy Subjects

Demmel, V.; Sandberg-Schaal, Anne; Jacobsen, Jacob; Golor, Georg; Pettersson, Jonas; Flint, Anne

doi:10.1007/s13300-018-0442-0

Cited by 12 publications

(12 citation statements)

References 36 publications

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“…Most novel drugs also undergo testing for their effect on the QT interval, as QT prolongation is a marker for potential ventricular fibrillation. Compared with placebo, subcutaneous semaglutide had no effect on this ECG measure in healthy volunteers, with doses above what is used in daily practice ( 113 ).…”

Section: Adverse Effects Of Semaglutidementioning

confidence: 99%

Safety of Semaglutide

2021

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The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

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Section: Adverse Effects Of Semaglutidementioning

confidence: 99%

Safety of Semaglutide

2021

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“…Since metformin, insulin, sulfonylureas or thiazolidinedione were marketed years before the regulations about arrhythmic safety, TQT studies did not evaluate these classic antidiabetics. On the contrary, newer drugs approved after the ICH E14 guideline, such as semaglutide, have been examined in TQT studies ( Demmel et al, 2018 ). However, evaluation of glucose lowering drugs is very challenging since, for instance, changes in blood glucose concentrations per se may correlate with prolonged QTc ( Suys et al, 2006 ).…”

Section: Safety Assessment Of Antidiabetic Drugsmentioning

confidence: 99%

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

et al. 2021

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Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.

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“…These findings complement those of a thorough QT/QTc study with s.c. semaglutide in 168 healthy subjects [ 15 ]. In the s.c. semaglutide study, there was no prolongation of the QTc interval at a supratherapeutic dose, with the upper limits of two-sided 90% CIs of the time-matched baseline-adjusted differences between semaglutide and placebo in QTcF and QT interval corrected individually for HR (QTcI) observed to be < 10 ms at all time points.…”

Section: Discussionmentioning

confidence: 99%

“…Where possible, these guidelines recommend testing drugs at levels substantially exceeding the anticipated maximum therapeutic exposure. A previous study showed that s.c. semaglutide at supratherapeutic doses does not result in a QTc interval prolongation in healthy subjects [ 15 ]. The level of exposure achieved with s.c. semaglutide is also expected to be supratherapeutic for the oral formulation.…”

Section: Introductionmentioning

confidence: 99%

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

Granhall

Bækdal

Breitschaft³

et al. 2021

Diabetes Ther

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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.

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No QTc Prolongation with Semaglutide: A Thorough QT Study in Healthy Subjects

Cited by 12 publications

References 36 publications

Safety of Semaglutide

Safety of Semaglutide

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

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

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